ORCID Profile
0000-0001-8976-619X
Current Organisation
Queensland University of Technology
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Publisher: Springer Science and Business Media LLC
Date: 12-2011
Abstract: It is well established that COMT is a strong candidate gene for substance use disorder and schizophrenia. Recently we identified two SNPs in COMT (rs4680 and rs165774) that are associated with schizophrenia in an Australian cohort. In iduals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. Association of both rs4680 and rs165774 with substance dependence, a common comorbidity of schizophrenia has not been investigated. To determine whether COMT is important in substance dependence, rs165774 and rs4680 were genotyped and haplotyped in patients with nicotine, alcohol and opiate dependence. The rs165774 SNP was associated with alcohol dependence. However, it was not associated with nicotine or opiate dependence. In iduals with alcohol dependence were more than twice as likely to carry the GG or AG genotypes compared to the AA genotype, indicating a dominant mode of inheritance. The rs4680 SNP showed a weak association with alcohol dependence at the allele level that did not reach significance at the genotype level but it was not associated with nicotine or opiate dependence. Analysis of rs165774/rs4680 haplotypes also revealed association with alcohol dependence with the G/G haplotype being almost 1.5 times more common in alcohol-dependent cases. Our study provides further support for the importance of the COMT in alcohol dependence in addition to schizophrenia. It is possible that the rs165774 SNP, in combination with rs4680, results in a common molecular variant of COMT that contributes to schizophrenia and alcohol dependence susceptibility. This is potentially important for future studies of comorbidity. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.
Publisher: Hindawi Limited
Date: 1993
Abstract: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of arylsulfatase A (ARSA EC 3.1.6.8). The 8 ARSA exons and adjacent intron boundaries from a patient with late-infantile metachromatic leukodystrophy were polymerase chain reaction (PCR) lified in seven discrete reactions. Amplified ARSA exons were analysed for the presence of sequence alterations by single-strand conformation polymorphism analysis, followed by direct sequencing of PCR products. The patient was found to be homozygous for a C-->T transition in exon IV that results in the substitution of a highly conserved threonine residue at amino acid 274 with a methionine (T274M). Analysis of a further 29 MLD patients revealed the presence of five additional homozygotes for T274M. All 6 T274M homozygotes (representing four families) were of Lebanese descent, and all were known to be the result of consanguineous marriages. The altered amino acid is rigidly conserved among 10 sulfatases from Escherichia coli to humans therefore, it is most likely that the resultant mutant protein will have little or no enzyme activity. This is consistent with the very low ARSA activity measured in these patients and their uniformly severe clinical presentation.
Publisher: Wiley
Date: 25-09-1995
Publisher: Springer Science and Business Media LLC
Date: 12-1995
DOI: 10.1038/NG1295-465
Abstract: Sanfilippo A syndrome is one of four recognised Sanfilippo sub-types (A, B, C and D) that result from deficiencies of different enzymes involved in the lysosomal degradation of heparan sulphate patients suffer from severe neurological disorders. The Sanfilippo syndrome sub-types are also known as mucopolysaccharidosis (MPS) type III (MPS-IIIA, B, C and D), and are part of the large group of lysosomal storage disorders. Each of the MPS-III types is inherited as an autosomal recessive disorder with considerable variation in severity of clinical phenotype. The incidence of Sanfilippo syndrome has been estimated at 1:24,000 in The Netherlands with MPS IIIA (MIM #252900) the most common. MPS-IIIA is the predominant MPS-III in the United Kingdom, and has a similar high incidence to that found in The Netherlands (E. Wraith, personal communication). There is a particularly high incidence of a clinically severe form of MPS-IIIA in the Cayman Islands with a carrier frequency of 0.1 (ref. 4). Due to the mild somatic disease compared to other MPS disorders there is difficulty in diagnosing mild cases of MPS-III, hence Sanfilippo syndrome may be underdiagnosed, especially in patients with mild mental retardation. Here, we report the isolation, sequence and expression of cDNA clones encoding the enzyme sulphamidase (EC 3.10.1.1). In addition, we report the chromosomal localisation of the sulphamidase gene as being 17q25.3. An 11-bp deletion, present in sulphamidase cDNA from two unrelated Sanfilippo A patients, is described.
Publisher: Wiley
Date: 10-05-1993
DOI: 10.1007/BF00711520
Publisher: Hindawi Limited
Date: 1992
Abstract: Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive genetic disease caused by a deficiency of the glycosidase alpha-L-iduronidase which is required for the lysosomal degradation of the glycosaminoglycans heparan sulfate and dermatan sulfate. Patients with MPS-I store these partially degraded glycosaminoglycans in their lysosomes. MPS-I patients have a wide range of clinical presentations, that makes it difficult to predict patient phenotype which is needed for genetic counselling and also impedes the selection and evaluation of patients undergoing therapy such as bone marrow transplantation. We report the presence of a common mutation accounting for 31% of MPS-I alleles in a study of 64 MPS-I patients. The mutation was originally detected by chemical cleavage and then direct PCR sequencing. The mutation is a single base substitution that introduces a stop codon at position 402 (W402X) of the alpha-L-iduronidase protein and is associated with an extremely severe clinical phenotype in homozygotes. Patients who are compound heterozygotes having one allele carrying the W402X mutation have a wide range of clinical phenotypes. Based on polymorphisms within the alpha-L-iduronidase gene, W402X is associated with three different haplotypes, implying that there is more than one origin for the mutation or that intragenic recombination has occurred. W402X introduces a MaeI restriction endonuclease site into MPS-I alleles enabling its simple detection, which should make possible the assessment of the efficacy of bone marrow transplantation in MPS-I patients homozygous for W402X.
Publisher: Elsevier BV
Date: 12-1990
Publisher: Elsevier BV
Date: 1982
DOI: 10.1016/0006-8993(82)90628-X
Abstract: The radioligand [3H]quinuclidinyl benzilate has been used to examine the muscarinic receptor population of the chick expansor secundariorum muscle during its post-hatch development. At hatch the muscle bound 0.165 fmol of the ligand, but during the following two weeks binding decreased rapidly. Further reduction in ligand binding to the adult stage was observed, but at a much slower rate. The developmental loss of binding sites within this tissue corresponds to previously demonstrated reduction in acetylcholine sensitivity.
Publisher: Elsevier BV
Date: 06-1997
Publisher: Oxford University Press (OUP)
Date: 1987
Abstract: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1-5, vincristine 0.7 mg m(-2) day 5, mitomycin 7 mg m(-2) day 5, cisplatin 14 mg m(-2) days 1-5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival. A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80% P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85). Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.
Publisher: Springer Science and Business Media LLC
Date: 04-09-2017
DOI: 10.1038/S41537-017-0026-4
Abstract: Epigenetic aging is associated with several biological mechanisms and diseases. We assessed two brain data sets, one small ( n = 48) and one large ( n = 392), to test epigenetic aging in schizophrenia. DNA methylation age from frontal cortex was significantly correlated with chronological age but no significant differences in DNA methylation age acceleration between schizophrenia cases and controls were observed in both data sets. Our results were consistent with a previous study investigating schizophrenia and epigenetic aging in superior temporal gyrus. Future studies targeting different brain regions and defined cell types are warranted to further investigate accelerated brain aging in schizophrenia.
Publisher: Oxford University Press (OUP)
Date: 1994
DOI: 10.1093/HMG/3.6.861
Abstract: A group of 46 European patients with mucopolysaccharidosis type I (MPS I) was screened for mutations of the alpha-L-iduronidase gene. The 2 common nonsense mutations, W402X and Q70X, were identified in, respectively, 37% and 35% of mutant alleles. Considerable differences were seen in the frequency of these 2 mutations in patients from North Europe (Norway and Finland) and other European countries (mainly The Netherlands and Germany). In Scandinavia, W402X and Q70X account for 17% and 62% of the MPS I alleles, respectively, while in other European countries W402X is about 2.5 times more frequent (48%) than Q70X (19%). Eight novel mutations are described including 4 missense mutations, 1 nonsense mutation, 1 insertion of 2 base pairs, and 2 deletions of 1 and 12 base pairs.
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.SCHRES.2004.08.020
Abstract: The T allele of the human dopamine D2 receptor (DRD2) gene C957T polymorphism is associated with reduced mRNA translation and stability. This results in decreased dopamine induced DRD2 upregulation and decreased in vivo D2 dopamine binding. Conversely, the C allele of the C957T polymorphism is not associated with such changes in mRNA leading to increased DRD2 expression. PET and postmortem binding studies show that schizophrenia is often associated with increased DRD2 availability. We report that on the basis of comparing the frequencies of the C/C and T/T genotypes of 153 patients with schizophrenia and 148 controls that schizophrenia is associated with the C/C genotype. The C957T shows a population attributable risk for schizophrenia of 24% and an attributable risk in those with schizophrenia of 42%. Increased expression of D2 receptors associated with the C allele is likely to be important in the underlying pathophysiology of at least some forms of schizophrenia. Enhanced understanding of schizophrenia afforded by this finding may lead to advances in treatment and prevention.
Publisher: Springer Science and Business Media LLC
Date: 03-1992
DOI: 10.1007/BF02265303
Publisher: Elsevier BV
Date: 10-2008
Publisher: American Medical Association (AMA)
Date: 11-2012
DOI: 10.1001/ARCHOPHTHALMOL.2012.1940
Abstract: OBJECTIVES To determine whether there is a difference in neuroretinal function and in macular pigment optical density between persons with high- and low-risk gene variants for age-related macular degeneration (AMD) and no ophthalmoscopic signs of AMD, and to compare the results on neuroretinal function to patients with manifest early AMD. METHODS Neuroretinal function was assessed with the multifocal electroretinogram for 32 participants (22 healthy persons with no AMD and 10 patients with early AMD). The 22 healthy participants with no AMD had either high- or low-risk genotypes for CFH (rs380390) and/or ARMS2 (rs10490924). Trough-to-peak response densities and peak-implicit times were analyzed in 5 concentric rings. Macular pigment optical density was assessed by use of customized heterochromatic flicker photometry. RESULTS Trough-to-peak response densities for concentric rings 1 to 3 were, on average, significantly greater in participants with high-risk genotypes than in participants with low-risk genotypes and in persons with early AMD after correction for age and smoking (P .05). The group peak-implicit times for ring 1 were, on average, delayed in the patients with early AMD compared with the participants with high- or low-risk genotypes, although these differences were not significant. There was no significant correlation between genotypes and macular pigment optical density. CONCLUSIONS Increased neuroretinal activity in persons who carry high-risk AMD genotypes may be due to genetically determined subclinical inflammatory and/or histological changes in the retina. Neuroretinal function in healthy persons genetically susceptible to AMD may be a useful additional early biomarker (in combination with genetics) of AMD before there is a clinical manifestation.
Publisher: Elsevier BV
Date: 10-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 11-1991
Abstract: alpha-L-Iduronidase (IDUA EC 3.2.1.76) is a lysosomal hydrolase in the metabolic pathway responsible for the degradation of the glycosaminoglycans heparan sulfate and dermatan sulfate. A deficiency of IDUA in humans leads to the accumulation of these glycosaminoglycans and results in the lysosomal storage disorder mucopolysaccharidosis type I. We have isolated and sequenced cDNA clones containing part of the human IDUA coding region and used PCR from reverse-transcribed RNA to obtain the full IDUA sequence. Analysis of the predicted 653-amino acid precursor protein shows that IDUA has a 26-amino acid signal peptide that is cleaved immediately prior to the amino terminus of the 74-kDa polypeptide present in human liver IDUA. The protein sequence contains six potential N-glycosylation sites. Northern blot analysis with IDUA cDNA detected only a single 2.3-kilobase mRNA species in human placental RNA however, PCR analysis of fibroblast, liver, kidney, and placental RNA showed the existence of alternatively spliced mRNA from the IDUA gene. Southern blot analysis failed to detect major deletions or gene rearrangements in any of the 40 mucopolysaccharidosis type I patients studied. Expression of a full-length IDUA cDNA construct in Chinese hamster ovary cells produced human IDUA protein at a level 13-fold higher than, and with a specific activity comparable to, IDUA present in normal human fibroblasts.
Publisher: Hindawi Limited
Date: 1995
Abstract: Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive disease caused by mutations in the alpha-L-iduronidase (IDUA) gene. These mutations lead to a deficiency of the glycosidase alpha-L-iduronidase (IDUA), which is required for the degradation of heparan sulphate and dermatan sulphate and thus the storage of these glycosaminoglycans in the lysosome. There is a wide range of clinical phenotypes in MPS-I (eponyms: Hurler syndrome, severe Hurler/Scheie syndrome, intermediate Scheie syndrome, mild), which makes prediction of disease severity and genetic counselling difficult. However, since cloning of the IDUA gene, mutation analysis has provided some molecular explanations for the range of MPS-I phenotypes, in turn facilitating the selection and evaluation of patients undergoing experimental treatment protocols such as bone marrow transplantation. A total of 46 mutations now have been defined for MPS-I consisting of 8 nonsense mutations, 21 missense mutations, 3 splice site mutations, and 14 minor deletions and/or insertions. Furthermore, 30 polymorphisms or nonpathogenic sequence variants have been defined, including 7 amino acid substitutions. Among patients of European origin, there are two major MPS-I mutations and a number of less frequent mutations. It is possible to follow mutation analysis of 292 patients, which can be ided into eight main patient groups of different ethnic and/or geographic origin with significant variation in mutant allele frequencies. A complex picture of molecular heterogeneity is emerging, building a valuable database for genotype henotype correlation. Mutation analysis is also providing some of the first clues into the structure and function of IDUA.
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.BBRC.2004.12.188
Abstract: Saturated fat plays a role in common debilitating diseases such as obesity, type 2 diabetes, and coronary heart disease. It is also clear that certain fatty acids act as regulators of metabolism via both direct and indirect signalling of target tissues. As the molecular mechanisms of saturated fatty acid signalling in the liver are poorly defined, hepatic gene expression analysis was undertaken in a human hepatocyte cell line after incubation with palmitate. Profiling of mRNA expression using cDNA microarray analysis revealed that 162 of approximately 18,000 genes tested were differentially expressed after incubation with palmitate for 48 h. Altered transcription profiles were observed in a wide variety of genes, including genes involved in lipid and cholesterol transport, cholesterol catabolism, cell growth and proliferation, cell signalling, beta-oxidation, and oxidative stress response. While palmitate signalling has been examined in pancreatic beta-cells, this is the first report showing that palmitate regulates expression of numerous genes via direct molecular signalling mechanisms in liver cells.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Springer Science and Business Media LLC
Date: 2008
Publisher: Elsevier BV
Date: 09-1993
Abstract: Deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS EC 3.1.6.13) results in the storage of the glycosaminoglycans heparan sulfate and dermatan sulfate, which leads to the lysosomal storage disorder mucopolysaccharidosis type II. Three overlapping genomic clones derived from an X-chromosome-specific library containing the entire IDS gene were isolated and the sequences of the intron boundaries and the 5' promoter region were determined. The IDS gene is split into nine exons spanning approximately 24 kb. The potential promoter for IDS lacks a TATA box but contains GC box consensus sequences, consistent with its role as a housekeeping gene. A polypyrimidine-like repeat is found in intron 1.
Publisher: Wiley
Date: 15-01-1994
Abstract: Gaucher disease is the most common lysosomal storage disease. It is an autosomal recessive disorder that results from a deficiency of beta-glucocerebrosidase. Three clinical phenotypes have been described: non-neuronopathic, acute neuronopathic, and subacute neuronopathic. Genomic DNA from 28 Australasian patients of erse ethnic origin with Gaucher disease was screened for 3 common mutations (1226G, 1448C and 84GG) using the lification refractory mutation system (ARMS), and one uncommon mutation (1504T) by restriction enzyme digestion. Thirty-eight of the 56 independent alleles in these patients were characterized, with 1448C present in 42% and 1226G in 28% of the alleles. The 1226G mutation was associated only with the non-neuronopathic phenotype and 7 of the 15 patients who carried the 1448C mutation developed neuronopathic disease. Three infants who died in the neonatal period following a rapidly progressive neurodegenerative course carried no identifiable mutations. The 84GG mutation was carried by 2 Jewish patients and 1504T was present in one patient. It is now possible to rapidly identify the common Gaucher mutations using ARMS and restriction enzyme digestion, and our findings confirm the heterogeneity of mutations in Gaucher disease. It is also possible to predict in part the phenotypic outcome when screening patients for these mutations. We consider mutation analysis to be of most use in prenatal diagnosis and for carrier detection within affected families.
Publisher: Springer Science and Business Media LLC
Date: 1992
DOI: 10.1007/BF00355837
Abstract: In a screen for gene copy-number changes in mouse mammary tumors, we identified a tumor with a small 350-kb licon from a region that is syntenic to a much larger locus lified in human cancers at chromosome 11q22. The mouse licon contains only one known gene, Yap, encoding the mammalian ortholog of Drosophila Yorkie (Yki), a downstream effector of the Hippo(Hpo)-Salvador(Sav)-Warts(Wts) signaling cascade, recently identified in flies as a critical regulator of cellular proliferation and apoptosis. In nontransformed mammary epithelial cells, overexpression of human YAP induces epithelial-to-mesenchymal transition, suppression of apoptosis, growth factor-independent proliferation, and anchorage-independent growth in soft agar. Together, these observations point to a potential oncogenic role for YAP in 11q22- lified human cancers, and they suggest that this highly conserved signaling pathway identified in Drosophila regulates both cellular proliferation and apoptosis in mammalian epithelial cells.
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.PSYCHRES.2011.09.024
Abstract: To test the importance of the dopamine D2 receptor (DRD2) region in nicotine dependence, 150 smokers and 228 controls were genotyped for the DRD2 C957T, -141delC and ANKK1 TaqIA polymorphisms (rs6277, rs1799732 and rs1800497, respectively). The -141delC SNP did not show any association but both the C957T and TaqIA SNPs showed association at the allele, genotype, haplotype and combined genotype levels. The 957C/TaqI A1 haplotype was more than 3.5 times as likely to be associated with nicotine dependence compared with the 957T/TaqI A1 haplotype (P=0.003). Analysis of the combined genotypes of both SNPs revealed that in iduals who were homozygous for the 957C-allele (CC) and had either one or two copies of the TaqI A1-allele were 3.3 times as likely to have nicotine dependence compared to all other genotype combinations (P=0.0003) and that these genotypes accounted for approximately 13% of the susceptibility to nicotine addiction in our population. Our findings suggest that the DRD2 C957T polymorphism and the ANKK1 TaqIA polymorphism are key contributors to the genetic susceptibility to nicotine dependence.
Publisher: Oxford University Press (OUP)
Date: 11-05-2012
Abstract: As recent conflicting reports describe a genetic association between both the C- and the T-alleles of the dopamine D2 receptor (DRD2) C957T polymorphism (rs6277) in alcohol-dependent subjects, our aim was to examine this polymorphism and TaqIA (rs1800497) in Australian alcohol-dependent subjects. The C957T polymorphism was genotyped in 228 patients with alcohol dependence (72 females and 156 males) and 228 healthy controls. The C-allele and C/C genotype of C957T was associated with alcohol dependence, whereas the TaqIA polymorphism was not. When analysed separately for C957T, males showed an even stronger association with the C-allele and females showed no association. The C957T and TaqIA haplotyping revealed a strong association with alcohol dependence and a double-genotype analysis (combining C957T and TaqIA genotypes) revealed that the relative risk of different genotypes varied by up to 27-fold with the TT/A1A2 having an 8.5-fold lower risk of alcohol dependence than other genotypes. Decreased DRD2 binding associated with the C-allele of the DRD2 C957T polymorphism is likely to be important in the underlying pathophysiology of at least some forms of alcohol dependence, and this effect appears to be limited to males only.
Publisher: Elsevier BV
Date: 28-10-2011
DOI: 10.1016/J.DRUGALCDEP.2010.08.014
Abstract: The C allele of a common polymorphism of the serotonin 2A receptor (HTR2A) gene, T102C, results in reduced synthesis of 5-HT2A receptors and has been associated with current smoking status in adults. The -1438A/G polymorphism, located in the regulatory region of this gene, is in linkage disequilibrium with T102C, and the A allele is associated with increased promoter activity and with smoking in adult males. We investigated the contributions of the HTR2A gene, chronic psychological stress, and impulsivity to the prediction of cigarette smoking status and dependence in young adults. T102C and -1438A/G genotyping was conducted on 132 healthy Caucasian young adults (47 smokers) who completed self-report measures of chronic stress, depressive symptoms, impulsive personality and cigarette use. A logistic regression analysis of current cigarette smoker user status, after adjusting for gender, depressive symptom severity and chronic stress, indicated that the T102C TT genotype relative to the CC genotype (OR=7.53), and lower punishment sensitivity (OR=0.91) were each significant predictive risk factors. However, for number of cigarettes smoked, only lower punishment sensitivity was a significant predictor (OR=0.81). These data indicate the importance of the T102C polymorphism to tobacco use but not number of cigarettes smoked for Caucasian young adults. Future studies should examine whether this is explained by effects of nicotine on the serotonin system. Lower punishment sensitivity increased risk of both smoking and of greater consumption, perhaps via a reduced sensitivity to cigarette health warnings and negative physiological effects.
Publisher: Springer Science and Business Media LLC
Date: 03-1991
DOI: 10.1007/BF00194643
Publisher: Springer Science and Business Media LLC
Date: 04-1982
DOI: 10.1038/296569A0
Publisher: Springer Science and Business Media LLC
Date: 06-1988
DOI: 10.1007/BF00280560
Abstract: The purpose of the present study was to use brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) to identify the mechanism of stroke in patients with Takayasu's arteritis (TA). Among a retrospective cohort of 190 TA patients, 21 (3 males and 18 females) with a mean age of 39.9 years (range 15-68 years) who had acute cerebral infarctions were included in lesion pattern analyses. The patients' characteristics were reviewed, and infarction patterns and the degree of cerebral artery stenosis were evaluated. Ischemic lesions were categorized into five subgroups: cortical border-zone, internal border-zone, large lobar, large deep, and small subcortical infarctions. In total, 21 ischemic stroke events with relevant ischemic lesions on MRI were observed. The frequencies of the lesion types were as follows: large lobar (n=7, 33.3%), cortical border zone (n=6, 28.6%), internal border zone (n=1, 4.8%), small cortical (n=0, 0%), and large deep (n=7, 33.3%). MRA revealed that 11 patients had intracranial artery stenosis. Hemodynamic compromise in large-artery stenosis and thromboembolic mechanisms play significant roles in ischemic stroke associated with TA.
Publisher: Oxford University Press (OUP)
Date: 08-1998
DOI: 10.1093/HMG/7.8.1215
Abstract: Metachromatic leukodystrophy (MLD) is an inborn error of myelin metabolism caused by a deficiency of the lysosomal hydrolase, arylsulfatase A (ASA). About 1% of the normal population have ASA activity levels approximating those of MLD patients. This non-pathogenic reduction in ASA activity is caused by homozygosity for the ASA pseudodeficiency allele (ASA-PD). Although this allele contains two sequence alterations, a polyadenylation defect and an amino acid substitution (N350S), the reduction in ASA activity previously has been attributed to the polyadenylation defect which reduces the amount of ASA mRNA and hence ASA protein by approximately 90%. The identification of MLD patients who are homozygous for the ASA-PD allele has brought about the need to re-evaluate the allele in light of the possible role that it may play in the development and progression of disease. Ribonuclease protection assay analysis of ASA mRNA transcripts and an investigation into the activity and lysosomal localization of protein expressed by an ASA expression construct containing the N350S variant indicated that both the N350S and polyadenylation defects play a role in biochemically defining the ASA-PD phenotype. The combined effect of the reduction in ASA mRNA due to the polyadenylation defect and the lowering of ASA activity and aberrant targeting of the expressed N350S ASA protein to the lysosome is estimated to reduce ASA activity in pseudodeficiency homozygotes to approximately 8% of normal.
Publisher: Elsevier BV
Date: 1992
DOI: 10.1016/0888-7543(92)90405-H
Abstract: A recently isolated cDNA clone from the iduronate sulfatase (IDS) gene has been used both to seed a contig of overlapping yeast artificial chromosomes (YACs) and to investigate the molecular defect in patients with Hunter syndrome (MPS II). Six YAC clones were found to span the IDS gene, and those and 14 other YACs were assembled into a 1.2-Mb contig around the gene in Xq27-q28. The physical map of the region identifies several putative CpG islands, suggesting the presence of other genes in the vicinity. DNA from a patient with a translocation breakpoint in the gene also permitted the orientation of the contig in the chromosome. Southern analysis of DNA from 25 unrelated Italian Hunter syndrome patients revealed 4 with deletions or rearrangements in the IDS gene.
Publisher: Elsevier BV
Date: 08-1992
DOI: 10.1016/0888-7543(92)90053-U
Abstract: In humans, a deficiency of the lysosomal hydrolase alpha-L-iduronidase (IDUA EC 3.2.1.76) results in the lysosomal storage of the glycosaminoglycans heparan sulfate and dermatan sulfate, thereby causing the lysosomal storage disorder mucopolysaccharidosis type I. The gene for IDUA is split into 14 exons spanning approximately 19 kb. We report the sequence of two non-contiguous segments of the IDUA gene, one 1.8-kb segment containing exons 1 and 2 and surrounding sequences and a second segment of 4.5 kb containing the last 12 exons. The potential promoter for IDUA has only GC box type consensus sequences consistent with a housekeeping promoter and is bounded by an Alu repeat sequence. The first two exons of IDUA are separated by an intron of 566 bp, then there is a large intron of approximately 13 kb, and the last 12 exons are clustered within 4.5 kb. No consensus polyadenylation signal was found in the 3' untranslated region, although two variant polyadenylation signals are proposed.
Publisher: Springer Science and Business Media LLC
Date: 06-1991
DOI: 10.1007/BF00204183
Abstract: Dendritic cells (DCs) have been regarded as one of the effective antigen-presenting cells, but the relationship between DCs and lymphocytes, in particular natural killer (NK) cells, remains unclear. In this study, we evaluated how DCs interact with both lymphocytes and NK cells using a coculture system. The number of lymphocytes increased significantly when cocultured with DCs (1.8-fold increase). In particular, the proliferation of NK cells was prominent. Furthermore, the coculture of DCs with lymphocytes induced a marked increase in IL-12 and IFN-gamma secretion. When contact between the DCs and lymphocytes was prevented, the secretion of both IL-12 and IFN-gamma was markedly reduced. IFN-gamma production was completely blocked by an anti-IL-12 antibody, indicating that IFN-gamma secretion was dependent on IL-12 secretion. The stimulating effect of the DCs on the proliferation of the lymphocytes was partially suppressed by anti-IL-12 antibodies, and was completely attenuated when cellular contact was prevented. Furthermore, the NK cell proliferation induced by coculture with DCs was significantly blocked by the inhibition of the interaction of either CD40-CD40L or CD28-B7 molecule. The coculture with DCs enhanced NK activity by 40%, and this was partially suppressed by anti-IL-12 antibodies and was completely blocked by the inhibition of cell-to-cell contact. These results indicate that the activation of NK cells by DCs is partially mediated by IL-12 secretion, and that direct contact between DCs and NK cells play a major role in this response.
Publisher: SAGE Publications
Date: 31-10-2013
Abstract: Although the advent of atypical, second-generation antipsychotics (SGAs) has resulted in reduced likelihood of akathisia, this adverse effect remains a problem. It is known that extrapyramidal adverse effects are associated with increased drug occupancy of the dopamine 2 receptors (DRD2). The A1 allele of the DRD2/ANKK1, rs1800497, is associated with decreased striatal DRD2 density. The aim of this study was to identify whether the A1(T) allele of DRD2/ANKK1 was associated with akathisia (as measured by Barnes Akathisia Rating Scale) in a clinical s le of 234 patients who were treated with antipsychotic drugs. Definite akathisia (a score ≥ 2 in the global clinical assessment of akathisia) was significantly less common in subjects who were prescribed SGAs (16.8%) than those prescribed FGAs (47.6%), p 0.0001. Overall, 24.1% of A1+ patients (A1A2/A1A1) who were treated with SGAs had akathisia, compared to 10.8% of A1- (thus, A2A2) patients. A1+ patients who were administered SGAs also had higher global clinical assessment of akathisia scores than the A1- subjects ( p = 0.01). SGAs maintained their advantage over FGAs regarding akathisia, even in A1+ patients who were treated with SGAs. These results strongly suggested that A1+ variants of the DRD2/ANKK1 Taq1A allele do confer an associated risk for akathisia in patients who were treated with SGAs, and these variants may explain inconsistencies found across prior studies, when comparing FGAs and SGAs.
Publisher: Wiley
Date: 09-1990
Abstract: A child was tentatively diagnosed as having cystic fibrosis, based on neonatal presentation with severe gastrointestinal complications the diagnosis was not confirmed biochemically and no tissues were available for DNA analysis. The mother presented in her subsequent pregnancy, and microvillar enzyme analysis of cell-free amniotic fluid at both 18 and 20 weeks gestation gave equivocal results. The pregnancy was terminated voluntarily because of a trend towards abnormal enzyme assay results on the second amniocentesis. Retrospectively, fetal tissues were found to be homozygous for the most common mutation of the cystic fibrosis gene (delta F508), which confirmed the prenatal assessment and suggested that the first infant of the couple was probably also affected by the disease.
Publisher: Elsevier BV
Date: 04-1992
DOI: 10.1016/0888-7543(92)90314-I
Abstract: Murine X-linked genes corresponding to the human Fragile X (FMR1) and Hunter syndrome (IDS) loci have been mapped in an interspecific backcross between B6CBA-Aw-J/A-Bpa and Mus spretus using human cDNA clones. Pedigree analysis of recombinants from a total of 248 backcross progeny favors a gene order of (Cf-9, Mcf-2)-(Fmr-1)-Ids-Gabra3-Rsvp. Gene order is conserved between the species, although no fragile site has been detected in the mouse in this region of the murine X chromosome.
Publisher: Springer Science and Business Media LLC
Date: 11-1992
DOI: 10.1007/BF00220095
Abstract: This is only a report of progress, negative in parts, in a very elusive matter. Ptomaines are not responsible microörganisms only partly so. Further investigation is suggested along the lines of a search for possible heat-labile toxins.
Publisher: Elsevier BV
Date: 1991
DOI: 10.1016/0888-7543(91)90218-4
Abstract: The development of the human gene map in the region of the fragile X mutation (FRAXA) at Xq27 has been h ered by a lack of closely linked polymorphic loci. The polymorphic loci DXS369 (detected by probe RN1), DXS296 (VK21A, VK21C), and DXS304 (U6.2) have recently been mapped to within 5 cM of FRAXA. The order of loci near FRAXA has been defined on the basis of physical mapping studies as cen-F9-DXS105-DXS98-DXS369-DXS297-FRAXA-++ +DXS296-IDS-DXS304-DXS52-qter. The probe VK23B detected HindIII and XmnI restriction fragment length polymorphisms (RFLPs) at DXS297 with heterozygote frequencies of 0.34 and 0.49, respectively. An IDS cDNA probe, pc2S15, detected StuI and TaqI RFLPs at IDS with heterozygote frequencies of 0.50 and 0.08, respectively. Multipoint linkage analysis of these polymorphic loci in normal pedigrees indicated that the locus order was F9-(DXS105, DXS98)-(DXS369, DXS297)-(DXS293,IDS)-DXS304-DXS52. The recombination fractions between adjacent loci were F9-(0.058)-DXS105-(0.039)-DXS98-(0.123)-DXS369-(0.00)- DXS297-(0.057)-DXS296- (0.00)-IDS-(0.012)-DXS304-(0.120)-DXS52. This genetic map will provide the basis for further linkage studies of both the fragile X syndrome and other disorders mapped to Xq27-q28.
Publisher: American Society for Clinical Investigation
Date: 15-03-1997
DOI: 10.1172/JCI119303
Publisher: Oxford University Press (OUP)
Date: 1991
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.NUT.2006.03.005
Abstract: There is evidence from in vitro studies that fatty acids can inhibit glucose uptake in liver. However, it is uncertain whether this happens in vivo when the liver is exposed to high levels of glucose and insulin, in combination with fatty acids, after a mixed meal. This study determined the effects of a combination of fatty acids and insulin on glucokinase (GK) activity and glycolysis in primary rat hepatocytes. Hepatocytes were cultured with 15 mM glucose and 2 or 10 nM insulin in combination with the fatty acids palmitate, oleate, linoleate, eicosapentaenoic acid, or docosahexaenoic acid. Total GK activity and the proportion of GK in the active, unbound state were measured to determine the effect of fatty acid on the activity and cellular localization of GK. Glucose phosphorylation and glycolysis were measured in intact cells. Lactate and pyruvate synthesis and the accumulation of ketone bodies were also estimated. Palmitate and eicosapentaenoic acid lowered total GK activity in the presence of 2 nM insulin, but not with 10 nM insulin. In contrast, oleate, linoleate, and docosahexaenoic acid did not alter GK activity. None of the fatty acids tested inhibited glucose phosphorylation or glycolysis in intact rat hepatocytes. In addition, GK activity was unaffected by insulin concentration. Some fatty acids can act to inhibit GK activity in primary hepatocytes. However, there was no evidence that this decrease in GK activity impaired glucose phosphorylation or glycolysis. Glucose and high concentrations of insulin, which promote glucose uptake, appear to counteract any inhibitory action of fatty acids. Therefore, the presence of fatty acids in a normal mixed meal is likely to have little effect on the capacity of the liver to take up, phosphorylate, and oxidize glucose.
Publisher: Oxford University Press (OUP)
Date: 1993
DOI: 10.1093/HMG/2.9.1471
Abstract: Myocardial infarction (MI) rapidly impairs cardiac contractile function and instigates maladaptive remodeling leading to heart failure. Patient-specific models are a maturing technology for developing and determining therapeutic modalities for MI that require accurate descriptions of myocardial mechanics. While substantial tissue volume reductions of 15-20% during systole have been reported, myocardium is commonly modeled as incompressible. We developed a myocardial model to simulate experimentally-observed systolic volume reductions in an ovine model of MI. Sheep-specific simulations of the cardiac cycle were performed using both incompressible and compressible tissue material models, and with synchronous or measurement-guided contraction. The compressible tissue model with measurement-guided contraction gave best agreement with experimentally measured reductions in tissue volume at peak systole, ventricular kinematics, and wall thickness changes. The incompressible model predicted myofiber peak contractile stresses approximately double the compressible model (182.8 kPa, 107.4 kPa respectively). Compensatory changes in remaining normal myocardium with MI present required less increase of contractile stress in the compressible model than the incompressible model (32.1%, 53.5%, respectively). The compressible model therefore provided more accurate representation of ventricular kinematics and potentially more realistic computed active contraction levels in the simulated infarcted heart. Our findings suggest that myocardial compressibility should be incorporated into future cardiac models for improved accuracy.
Publisher: Proceedings of the National Academy of Sciences
Date: 11-1990
Abstract: Iduronate 2-sulfatase (IDS, EC 3.1.6.13) is required for the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations causing IDS deficiency in humans result in the lysosomal storage of these glycosaminoglycans and Hunter syndrome, an X chromosome-linked disease. We have isolated and sequenced a 2.3-kilobase cDNA clone coding for the entire sequence of human IDS. Analysis of the deduced 550-amino acid IDS precursor sequence indicates that IDS has a 25-amino acid amino-terminal signal sequence, followed by 8 amino acids that are removed from the proprotein. An internal proteolytic cleavage occurs to produce the mature IDS present in human liver shown to contain a 42-kDa polypeptide N-terminal to a 14-kDa polypeptide. The IDS sequence has strong sequence homology with other sulfatases (such as sea urchin arylsulfatase, human arylsulfatases A, B, and C, and human glucosamine 6-sulfatase), suggesting that the sulfatases comprise an evolutionarily related family of genes that arose by gene duplication and ergent evolution. The arylsulfatases have a greater homology with each other than with the non-arylsulfatases (IDS and glucosamine 6-sulfatase). The IDS cDNA detected RNA species of 5.7, 5.4, 2.1, and 1.4 kilobases in human placental RNA and revealed structural alterations and gross deletions of the IDS gene in many of the clinically severe Hunter syndrome patients studied.
Publisher: Cambridge University Press (CUP)
Date: 06-2015
DOI: 10.1016/J.EURPSY.2015.01.008
Abstract: Dystrobrevin binding protein 1 ( DTNBP1 ) is a schizophrenia susceptibility gene involved with neurotransmission regulation (especially dopamine and glutamate) and neurodevelopment. The gene is known to be associated with cognitive deficit phenotypes within schizophrenia. In our previous studies, DTNBP1 was found associated not only with schizophrenia but with other psychiatric disorders including psychotic depression, post-traumatic stress disorder, nicotine dependence and opiate dependence. These findings suggest that DNTBP1 may be involved in pathways that lead to multiple psychiatric phenotypes. In this study, we explored the association between DTNBP1 SNPs (single nucleotide polymorphisms) and multiple psychiatric phenotypes included in the Diagnostic Interview of Psychosis (DIP). Five DTNBP1 SNPs, rs17470454, rs1997679, rs4236167, rs9370822 and rs9370823, were genotyped in 235 schizophrenia subjects screened for various phenotypes in the domains of depression, mania, hallucinations, delusions, subjective thought disorder, behaviour and affect, and speech disorder. SNP-phenotype association was determined with ANOVA under general, dominant/recessive and over-dominance models. Post hoc tests determined that SNP rs1997679 was associated with visual hallucination SNP rs4236167 was associated with general auditory hallucination as well as specific features including non-verbal, abusive and third-person form auditory hallucinations and SNP rs9370822 was associated with visual and olfactory hallucinations. SNPs that survived correction for multiple testing were rs4236167 for third-person and abusive form auditory hallucinations and rs9370822 for olfactory hallucinations. These data suggest that DTNBP1 is likely to play a role in development of auditory related, visual and olfactory hallucinations which is consistent with evidence of DTNBP1 activity in the auditory processing regions, in visual processing and in the regulation of glutamate and dopamine activity.
Publisher: Oxford University Press (OUP)
Date: 1994
DOI: 10.1093/HMG/3.6.1019
Abstract: We prepared full thickness skin defects in rats fed on a protein-free diet as a hypoproteinaemia model, then switched the animals to a diet containing a normal protein level 1, 6 or 12 days after wounding (inflammatory, granulation and rearrangement phases of the wound healing process) to examine whether improvement in the low-protein state promotes subsequent wound healing. The interval until wound healing in rats fed on a normal protein diet was significantly shorter, whereas that in rats continuously fed on a protein-free diet was significantly longer than those of other groups. Early correction tended to accelerate wound healing. Although wound contraction in groups receiving a protein-corrected or protein-free diet remained similar until 15 days after wounding, thereafter the duration of the rearrangement phase was significantly longer in the protein-free group than in the other groups. The collagen level per unit of granulation tissue area during wound healing was significantly lower in the protein-free group than in the other groups. These findings indicate that protein correction at any time after wounding accelerates wound healing, although early correction is more effective, and reduces the duration of the rearrangement phase more than those of the inflammatory and granulation phases because of the deposit of collagen.
Publisher: Elsevier BV
Date: 07-1991
DOI: 10.1016/0888-7543(91)90438-K
Abstract: The fragile X syndrome locus, FRAXA, is located at Xq27. Until recently, few polymorphic loci had been genetically mapped close to FRAXA. This has been attributed to an increased frequency of recombination at Xq27, possibly associated with the fragile X mutation. In addition, the frequency of recombination around FRAXA has been reported to vary among fragile X families. These observations suggested that the genetic map at Xq27 in normal populations was different from that in fragile X populations and that the genetic map also varied within the fragile X population. Such variability would reduce the reliability of carrier risk estimates based on DNA studies in fragile X families. Five polymorphic loci have now been mapped to within 4 cM of FRAXA--DXS369, DXS297, DXS296, IDS, and DXS304. The frequency of recombination at Xq26-q28 was evaluated using data at these loci and at more distant loci from 112 families with the fragile X syndrome. Two-point and multipoint linkage analyses failed to detect any difference in the recombination fractions in fragile X versus normal families. Two-point and multipoint tests of linkage homogeneity failed to detect any evidence of linkage heterogeneity in the fragile X families. On the basis of this analysis, genetic maps derived from large s les of normal families and those derived from fragile X families are equally valid as the basis for calculating carrier risk estimates in a particular family.
Publisher: Hindawi Limited
Date: 05-04-2023
DOI: 10.1155/2023/7255395
Abstract: As part of a larger study examining the perceived impacts of health system stress in Queensland, Australia, caused by the COVID-19 pandemic, this study explored the experiences and perspectives of a s le of people with spinal cord injury (SCI) and critical stakeholders to identify secondary complications, access concerns, and potential solutions in the context of the pandemic. This study utilised a multimethods qualitative design. Thirty-four people with SCI completed an online survey between August and November 2021, recruited from an online Spinal Life Australia Peer Support Group. Sixteen SCI expert stakeholders, recruited from the Queensland Spinal Cord Injuries Services, consumer support organisations, and funding agencies, participated in one of two expert stakeholder forums in September 2021, focusing on impacts of the pandemic on the services they provided. Survey and forum results were analysed thematically. Results highlighted service disruption wherein people with SCI faced difficulty accessing health and community services (including rehabilitation) and personal supports. Reduced access led to secondary complications in physical health, psychosocial, and occupational domains. Solutions for safeguarding access to care, including action-ready back-up plans, effective technology and training, collaboration of service networks, and forward planning for system disruption, consumables access, staff support, and advocacy are required to best support vulnerable populations and the supporting staff in times of crisis. In conclusion, COVID-19 disrupted access to specialist SCI and mainstream health, rehabilitation, and social care services, resulting in functional decline and physical and psychosocial complications. While people with SCI and their service providers attempted to innovate and solve problems to overcome service access barriers, this is not possible in all situations. Improved planning and preparation for future system disruptions mitigates risks and better protects vulnerable populations and service providers in times of severe system stress.
Publisher: Oxford University Press (OUP)
Date: 08-2013
DOI: 10.1017/S1461145711001659
Abstract: Dysfunction of dopamine D3 receptors, particularly in the mesocorticolimbic system, has been linked to the pathogenesis of major depression. Preclinical data show enhanced D3 receptor binding in the striatum upon antidepressant medication and electroconvulsive therapy (ECT). Thus, the potential impact of dopamine D3 receptor gene (DRD3) variation on ECT outcome in treatment-resistant major depression was evaluated by applying a combined molecular and imaging genetic approach. Altogether, 10 representative variants covering 95.4% of DRD3 gene variation were investigated for association with response to ECT in a s le of 104 (71 female, 33 male) Caucasian patients with pharmacorefractory major depression. Additionally, ventral striatum responsiveness to happy faces was assessed in two independent s les of depressed patients (total N=54) by means of functional magnetic resonance imaging at 3 T. Significant association of DRD3 rs3732790, rs3773679 and rs9817063 variants with response (uncorrected p=0.02–0.03) and remission (uncorrected p=0.01) after ECT was discerned. Logistic regression analyses revealed association of rs3732790 (uncorrected p=0.009 corrected p=0.045) and rs3773679 (uncorrected p=0.009 corrected p=0.045) with remission when applying a recessive model of inheritance. The rs3732790T allele conferring a more favourable treatment response was furthermore found to be associated with stronger striatal responsiveness to happy facial expressions (s le 1: cluster-corrected p=0.002 s le 2: p=0.023). In summary, the present study suggests some impact of DRD3 gene variation on ECT response, potentially mediated by alteration of striatal engagement during the processing of emotionally rewarding stimuli.
Publisher: Hindawi Limited
Date: 1992
Abstract: Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive genetic disease caused by a deficiency of the glycosidase alpha-L-iduronidase which is required for the lysosomal degradation of the glycosaminoglycans heparan sulfate and dermatan sulfate. Patients with MPS-I store forms of these partially degraded glycosaminoglycans in their lysosomes. MPS-I patients present with a wide range of clinical phenotypes, which makes prognostic predictions and genetic counselling difficult, therefore impeding the selection and evaluation of patients undergoing experimental therapy, such as bone marrow transplantation. We report the presence of two mutations, one that introduces a stop codon at position 70 (Q70X), and the other that alters the proline at position 533 to an arginine (P533R) in the 653 amino acid alpha-L-iduronidase protein. These mutations were originally detected by chemical cleavage and then by direct PCR sequencing. Allele specific oligonucleotides were used to detect the mutations in a group of 73 MPS-I patients and Q70X was found to account for 15% of all MPS-I alleles and P533R for 3% of MPS-I alleles. Both mutations are associated with an extremely severe clinical phenotype in homozygotes. MPS-I patients heterozygous for either mutation may have a wide range of clinical phenotypes. We have now described three mutations, W402X (Scott et al., 1992c), Q70X, and P533R totalling 53% of MPS-I alleles which together define 28% of MPS-I genotypes.
Publisher: Elsevier BV
Date: 02-2018
Publisher: Hindawi Limited
Date: 1995
Abstract: ur preclinical findings replicated women's hypersensitivity to type-2 diabetes mellitus (T2DM)-evoked cardiac dysfunction along with demonstrating estrogen (E2)-dependent disruption of the cardiac adiponectin (APN)-connexin43 (Cx43) signaling. Whether the latter molecular anomaly underlies this women's cardiovascular health problem remains unknown. We hypothesized that restoration of the disrupted APN-Cx43 signaling alleviates this sex/E2-dependent cardiac dysfunction in diabetic female rats. To test this hypothesis, we administered the adiponectin receptor 1 (AdipoR1) agonist AdipoRon (30 mg/kg/d for 10 days) to female sham operated (SO) and ovariectomized (OVX) rats, which exhibited and lacked the T2DM left ventricular (LV) dysfunction, respectively, when fed high-fat diet and received low dose streptozotocin regimen nondiabetic control SO and OVX rats received control diet and vehicle for streptozotocin. In T2DM SO rats, LV dysfunction, AdipoRon mitigated: (1) LV hypertrophy, (2) reductions in fractional shortening, LV developed pressure, dP/dtmax, dP/dtmin, and Tau. In LV tissues of the same rats, AdipoRon reversed reduction in Cx43 and elevations in TNFα, heme-oxygenase 1 (HO-1), and circulating cardiovascular risk factor asymmetric dimethylarginine. The findings also revealed ovarian hormones independent effects of AdipoRon, which included d ening of the pro-oxidant enzyme HO-1. These novel findings yield new insight into a causal role for compromised APN-Cx43 signaling in the E2-dependent hypersensitivity to T2DM-evoked cardiac inflammation and dysfunction. Equally important, the findings identify restoration of Cx43 signaling as a viable therapeutic modality for alleviating this women's cardiovascular health-related problem.
Publisher: Hindawi Limited
Date: 2009
DOI: 10.1002/DA.20517
Abstract: Variations in genes related to the dopaminergic pathway have been implicated in neuropsychiatric disorders such as schizophrenia, substance misuse, Alzheimer's disease and Post Traumatic Stress Disorder (PTSD). A single nucleotide polymorphism (SNP) (957C>T) and a deletion polymorphism (-141delC) in the DRD2 gene and a SNP (Taq1A) in a gene directly downstream of DRD2 have all been implicated in dopamine functioning in the brain. To test the importance of these three polymorphisms in PTSD susceptibility, a genetic screen was performed in 127 war veterans diagnosed with PTSD and 228 control in iduals without a history of PTSD. No significant association was found between PTSD and the Taq1A or -141delC polymorphisms. However, a significant association was observed with PTSD and the 957C>T polymorphism. PTSD in iduals were more likely to carry the C allele compared to the controls (P=0.021). Our findings suggest that the 957C>T polymorphism in the DRD2 gene is one of the genetic factors for susceptibility to PTSD.
Publisher: Springer Science and Business Media LLC
Date: 12-2007
Abstract: Craniosynostosis, the premature fusion of calvarial sutures, is a common craniofacial abnormality. Causative mutations in more than 10 genes have been identified, involving fibroblast growth factor, transforming growth factor beta, and Eph/ephrin signalling pathways. Mutations affect each human calvarial suture (coronal, sagittal, metopic, and lambdoid) differently, suggesting different gene expression patterns exist in each human suture. To better understand the molecular control of human suture morphogenesis we used microarray analysis to identify genes differentially expressed during suture fusion in children with craniosynostosis. Expression differences were also analysed between each unfused suture type, between sutures from syndromic and non-syndromic craniosynostosis patients, and between unfused sutures from in iduals with and without craniosynostosis. We identified genes with increased expression in unfused sutures compared to fusing/fused sutures that may be pivotal to the maintenance of suture patency or in controlling early osteoblast differentiation (i.e. RBP4 , GPC3 , C1QTNF3 , IL11RA , PTN , POSTN ). In addition, we have identified genes with increased expression in fusing/fused suture tissue that we suggest could have a role in premature suture fusion (i.e. WIF1 , ANXA3 , CYFIP2 ). Proteins of two of these genes, glypican 3 and retinol binding protein 4, were investigated by immunohistochemistry and localised to the suture mesenchyme and osteogenic fronts of developing human calvaria, respectively, suggesting novel roles for these proteins in the maintenance of suture patency or in controlling early osteoblast differentiation. We show that there is limited difference in whole genome expression between sutures isolated from patients with syndromic and non-syndromic craniosynostosis and confirmed this by quantitative RT-PCR. Furthermore, distinct expression profiles for each unfused suture type were noted, with the metopic suture being most disparate. Finally, although calvarial bones are generally thought to grow without a cartilage precursor, we show histologically and by identification of cartilage-specific gene expression that cartilage may be involved in the morphogenesis of lambdoid and posterior sagittal sutures. This study has provided further insight into the complex signalling network which controls human calvarial suture morphogenesis and craniosynostosis. Identified genes are candidates for targeted therapeutic development and to screen for craniosynostosis-causing mutations.
Publisher: Elsevier BV
Date: 10-1989
DOI: 10.1016/0006-291X(89)91739-7
Abstract: The human lysosomal storage disorder fucosidosis results from the deficiency of alpha-L-fucosidase, a lysosomal enzyme essential for the catabolism of oligosaccharides containing alpha-L-fucosides. cDNA clones coding for human alpha-L-fucosidase have been isolated from lambda gt10 and lambda gt11 cDNA libraries derived from human liver, placenta and colon. Compilation of cDNA sequences results in a nucleotide sequence of 2053 base pairs encoding alpha-L-fucosidase. The sequence contains an open reading frame of 461 amino acids beginning with the first in-frame methionine and includes 439 amino acids which comprise the mature protein in addition to a hydrophobic signal peptide sequence of 22 amino acids.
Publisher: Wiley
Date: 05-1992
DOI: 10.1007/BF02435972
Publisher: Oxford University Press (OUP)
Date: 1993
Abstract: Mutations of the iduronate-2-sulfatase gene were identified in 16 patients with mucopolysaccharidosis type II (Hunter syndrome). Together with another 10 cases reported by us earlier it emerges that about 20% of the patients have deletions of the whole gene or other major structural alterations. One, two or three base pair deletions are found in about 23% of the cases while the remaining about 57% carry point mutations predicting amino acid replacement, premature termination of translation, or aberrant splicing. Molecular analysis of mRNA in splice site mutants showed that these latter defects frequently resulted in use of cryptic splice sites in exons or introns. 62% of the small deletions and point mutations have occurred in 3 of the 9 iduronate-2-sulfatase gene exons. Knowledge of the primary genetic defect allows fast and reliable carrier detection and prenatal diagnosis as well as insight into the relationship between genotype and phenotype.
Publisher: Springer Science and Business Media LLC
Date: 02-1991
DOI: 10.1007/BF00201841
Publisher: Hindawi Limited
Date: 1993
Abstract: A number of mutations in the X-chromosomal human iduronate-2-sulphatase gene have now been identified as the primary genetic defect leading to the clinical condition known as Hunter syndrome or mucopolysaccharidosis type II. The mutations that are tabulated include different deletions, splice-site and point mutations. From the group of 319 patients thus far studied by Southern analysis, 14 have a full deletion of the gene and 48 have a partial deletion or other gross rearrangements. All patients with full deletions or gross rearrangements have severe clinical presentations. Twenty-nine different "small" mutations have so far been characterised in a total of 32 patients. These include 4 nonsense and 13 missense mutations, 7 different small deletions from 1 to 3 bp, with most leading to a frameshift and premature chain termination, and 5 different splice-site mutations also leading to small insertions or deletions in the mRNA. A 60 bp deletion, that results from a new donor splice-site, has been observed in five unrelated patients with relatively mild clinical phenotypes. This information will not only be useful for MPS II patient and carrier diagnosis, but also will aid in the understanding of the structure and function of iduronate-2-sulphatase, and possibly in correlating genotype with phenotype.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2010
Abstract: A number of studies have found associations between dysbindin ( DTNBP1 ) polymorphisms and schizophrenia. Recently we identified a DTNBP1 SNP (rs9370822) that is strongly associated with schizophrenia. In iduals diagnosed with schizophrenia were nearly three times as likely to carry the CC genotype compared to the AA genotype. To investigate the importance of this SNP in the function of DTNBP1 , a number of psychiatric conditions including addictive behaviours and anxiety disorders were analysed for association with rs9370822. The DTNBP1 polymorphism was significantly associated with post-traumatic stress disorder (PTSD) as well as nicotine and opiate dependence but not alcohol dependence. In iduals suffering PTSD were more than three times as likely to carry the CC genotype compared to the AA genotype. In iduals with nicotine or opiate dependence were more than twice as likely to carry the CC genotype compared to the AA genotype. This study provides further support for the importance of DTNBP1 in psychiatric conditions and suggests that there is a common underlying molecular defect involving DTNBP1 that contributes to the development of several anxiety and addictive disorders that are generally recognised as separate clinical conditions. These disorders may actually be different expressions of a single metabolic pathway perturbation. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1111/J.1432-0436.2007.00244.X
Abstract: Craniosynostosis is the premature fusion of calvarial sutures. It results from abnormal differentiation or proliferation of cells within the osteogenic fronts of growing calvarial bones. To date, research has focused on animal models and in vitro organ and tissue culture to determine the molecular mechanisms controlling calvarial suture morphogenesis. Here, we test a new, in vivo-in vitro approach based on the hypothesis that calvarial suture cells passaged in minimal medium exhibit a stable gene expression profile similar to undifferentiated osteoblastic cells that can provide a benchmark for comparison with in vivo expression of differentiated tissue. We show that tissue-specific expression is lost after the first passage and, using cDNA microarrays, compare expression between fused suture tissue from craniosynostosis patients and in vitro de-differentiated explant cells. A large number of differentially expressed genes were identified, including novel genes WIF1, LEF1, SATB2, RARRES1, DEFA1, DMP1, PTPRZ1, and PTPRC, as well as those commonly associated with human suture morphogenesis, e.g., FGF2, MSX2, and BMP2. Two differentially expressed genes, WIF1 and FGF2, were further examined in an in vivo-in vivo comparison between unfused and prematurely fused tissue. The same pattern of differential expression was observed in each case, further validating the ability of our in vivo-in vitro approach to identify genes involved in in vivo human calvarial tissue differentiation.
Publisher: Springer Science and Business Media LLC
Date: 04-1989
DOI: 10.1007/BF00288275
Abstract: The significance of occupational violence in general practice is well established, but research has focused almost exclusively on the experiences of GPs. Only limited research has examined the role of general practice receptionists despite their acknowledged vulnerability to violent patient behaviour. No qualitative research has explored this problem. To explore the experiences of general practice receptionists regarding occupational violence and the effects of violence on their psychological and emotional wellbeing and on their work satisfaction and performance. Qualitative study. Constituent practices of an Australian network of research general practices. Practices were located in a range of socioeconomic settings. Semi-structured interviews were conducted with practice receptionists. The interviews were audiotaped, transcribed, and subjected to thematic analysis employing a process of constant comparison in which data collection and analysis were cumulative and concurrent. Qualitative written responses from a cross-sectional questionnaire-based study performed concurrently with the qualitative study were similarly analysed. Nineteen interviews were conducted and 12 written responses were received. Violence was found to be a common, sometimes pervasive, experience of many receptionists. Verbal abuse, both 'across the counter' and telephone abuse, was the most prominent form of violence, although other violence, including assault and threats with guns, was reported. Experiences of violence could have marked emotional and psychological effects and could adversely affect job satisfaction, performance, and commitment. It is apparent that occupational violence is a whole-of-practice problem and strategies for GP and staff safety will need to take a whole-of-practice approach.
Publisher: Oxford University Press (OUP)
Date: 03-07-2014
Abstract: The functional BDNF single nucleotide polymorphism (SNP) rs6265 has been associated with many disorders including schizophrenia and alcohol dependence. However, studies have been inconsistent, reporting both positive and negative associations. Comorbid alcohol dependence has a high prevalence in schizophrenia so we investigated the role of rs6265 in alcohol dependence in Australian populations of schizophrenia and alcohol-dependent patients. Two BDNF SNPs rs6265 and a nearby SNP rs7103411 were genotyped in a total of 848 in iduals. These included a schizophrenia group (n = 157) and a second schizophrenia replication group (n = 235), an alcohol-dependent group (n = 231) that had no schizophrenia diagnosis and a group of healthy controls (n = 225). Allelic association between rs7103411 and comorbid alcohol dependence was identified (P = 0.044) in the primary schizophrenia s le. In the replication study, we were able to detect allelic associations between both BDNF SNPs and comorbid alcohol dependence (rs6265, P = 0.006 rs7103411, P = 0.014). Moreover, we detected association between both SNPs and risk-taking behaviour after drinking (rs6265, P = 0.005 rs7103411, P = 0.009) and we detected strong association between both SNPs and alcohol dependence in males (rs6265, P = 0.009 rs7103411, P = 0.013) while females showed association with multiple behavioural measures reflecting repetitive alcohol consumption. Haplotype analysis revealed the rs6265-rs7103411 A/C haplotype is associated with comorbid alcohol dependence (P = 0.002). When these SNPs were tested in the non-schizophrenia alcohol-dependent group we were unable to detect association. We conclude that these BDNF SNPs play a role in development of comorbid alcohol dependence in schizophrenia while our data do not indicate that they play a role in alcohol-dependent patients who do not have schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 16-01-2009
DOI: 10.1007/S10519-008-9255-7
Abstract: The dopamine D2 receptor (DRD2) C957T polymorphism CC genotype is associated with decreased striatal binding of DRD2 and executive function and working memory impairments in healthy adults. We investigated the relationships between C957T and acute stress with behavioral phenotypes of impulsivity in 72 young adults randomly allocated to either an acute psychosocial stress or relaxation induction condition. Homozygotes for 957C showed increased reward responsiveness after stress induction. They were also quicker when making immediate choices on the delay discounting task when stressed, compared with homozygotes who were not stressed. No effects were found for response inhibition, a dimension of impulsivity not related to extrinsic rewards. These data suggest that C957T is associated with a reward-related impulsivity endophenotype in response to acute psychosocial stress. Future studies should examine whether the greater sensitivity of 957C homozygotes to the effects of stress is mediated through dopamine release.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 28-02-2011
DOI: 10.1167/IOVS.10-5967
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2001
DOI: 10.1097/00001721-200104000-00006
Abstract: Recently, a polymorphism was identified in exon 25 of the factor V gene that is possibly a functional candidate for the HR2 haplotype. This haplotype is characterized by a single base substitution named R2 (A4070G) in the B domain of the protein. A mutation (A6755G 2194Asp-->Gly) located near the C terminus has been hypothesized to influence protein folding and glycosylation, and might be responsible for the shift in factor V isoform (FV1 / FV2) ratio. This study investigated the prevalence of these two factor V HR2 haplotype polymorphisms in a cohort of normal blood donors, patients with osteoarthritis and women with complications during pregnancy, and in families of factor V Leiden in iduals. A high allele frequency for the two polymorphisms was found in the blood donor group (6.2% R2, 5.6% A6755G). No significant difference in allele frequency was observed in the clinical groups (obstetric complications and osteoarthritis, 4.1-4.9% for the two polymorphisms) when compared with that of healthy blood donors. We confirm that the factor V A6755G polymorphism shows strong linkage to the R2 allele, although it is not exclusively inherited with the exon 13 A4070G variant and can occur independently.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.JAD.2015.08.069
Abstract: The nitric oxide synthase 1 adaptor protein gene (NOS1AP) has previously been recognised as a schizophrenia susceptibility gene due to its role in glutamate neurotransmission. The gene is believed to inhibit nitric oxide (NO) production activated by the N-methyl-d-aspartate (NMDA) receptor and reduced NO levels have been observed in schizophrenia patients. However, association studies investigating NOS1AP and schizophrenia have produced inconsistent results, most likely because schizophrenia is a clinically heterogeneous disorder. This study aims to investigate the association between NOS1AP variants and defined depression phenotypes of schizophrenia. Nine NOS1AP SNPs, rs1415259, rs1415263, rs1858232, rs386231, rs4531275, rs4656355, rs4657178, rs6683968 and rs6704393 were genotyped in 235 schizophrenia subjects screened for various phenotypes of depression. One NOS1AP SNP (rs1858232) was associated with the broad diagnosis of schizophrenia and eight SNPs were associated with depression related phenotypes within schizophrenia. The rs1415259 SNP showed strong association with sleep dysregulation phenotypes of depression. Results suggest that NOS1AP variants are associated with various forms of depression in schizophrenia and are more prevalent in males. Schizophrenia is a clinically heterogeneous disease that can vary greatly between different ethnic and geographic populations so our observations should be viewed with caution until they are independently replicated, particularly in larger patient cohorts.
Publisher: Mary Ann Liebert Inc
Date: 02-2012
Abstract: Dopamine D2 receptor (DRD2) is thought to be critical in regulating the dopaminergic pathway in the brain, which is known to be important in the etiology of schizophrenia. It is, therefore, not surprising that most antipsychotic medication acts on DRD2. DRD2 is widely expressed in the brain levels are reduced in the brains of patients with schizophrenia, and DRD2 polymorphisms have been associated with reduced brain expression. We have previously identified a genetic variant in DRD2, rs6277 to be strongly implicated in schizophrenia susceptibility. To identity new associations in the DRD2 gene with disease status and clinical severity, we genotyped seven single-nucleotide polymorphisms (SNPs) in DRD2 by using a multiplex mass spectrometry method. SNPs were chosen by using a haplotype block-based gene-tagging approach so, the entire DRD2 gene was represented. One polymorphism, rs2734839 was found to be significantly associated with schizophrenia as well as late onset age. In iduals carrying the genetic variation were more than twice as likely to have schizophrenia compared with controls. Our results suggest that DRD2 genetic variation is a good indicator for schizophrenia risk and may also be used as a predictor of age of onset.
Publisher: Wiley
Date: 19-09-2009
DOI: 10.1002/JCP.21586
Abstract: Osteogenic supplements are a requirement for osteoblastic cell differentiation during in vitro culture of human calvarial suture-derived cell populations. We investigated the ability of ascorbic acid and beta-glycerophosphate with and without the addition of dexamethasone to stimulate in vivo-like osteoblastic differentiation. Cells were isolated from unfused and prematurely fused suture tissue from patients with syndromic and non-syndromic craniosynostosis and cultured in each osteogenic medium for varying lengths of time. The effect of media supplementation was investigated with respect to the ability of cells to form mineralised bone nodules and the expression of five osteodifferentiation marker genes (COL1A1, ALP, BSP, OC and RUNX2), and five genes that are differentially expressed during human premature suture fusion (GPC3, RBP4, C1QTNF3, WIF1 and FGF2). Cells from unfused sutures responded more slowly to osteogenic media but formed comparable bone nodules to fused suture-derived cells after 16 days of culture in either osteogenic media. However, gene expression differed between unfused and fused suture-derived cells, as did expression in each osteogenic medium. When compared to expression in the explant tissue of origin, neither medium induced a level or profile of gene expression similar to that seen in vivo. Overall, our results demonstrate that cells from the same suture that are isolated during different stages of morphogenesis in vivo, despite being de-differentiated to a similar level in vitro, respond uniquely and differently to each osteogenic medium. Further, we suggest that neither cell culture medium recapitulates differentiation via activation of the same genetic cascades as occurs in vivo.
Publisher: Oxford University Press (OUP)
Date: 1991
Abstract: Acetylcholinesterase (AChE) is a secreted enzyme essential for regulating cholinergic neurotransmission at neuronal and neuromuscular synapses. In view of the altered expression of AChE in some central neurological and neuromuscular disorders with a probable genetic basis, we have identified the chromosomal location of the gene encoding AChE. Chromosomal in situ suppression hybridization analysis revealed a single gene to be at 7q22, a result which was confirmed by PCR analysis of genomic DNA from a human/hamster somatic cell hybrid containing a single human chromosome 7. The AChE gene thus maps to the same region in which frequent nonrandom chromosome 7 deletions occur in leukemias of myeloid cell precursors known to express the enzyme during normal differentiation.
Publisher: Cambridge University Press (CUP)
Date: 10-2010
DOI: 10.1016/J.EURPSY.2009.11.011
Abstract: Dystrobrevin binding protein 1 ( DTNBP1 ), or dysbindin, is thought to be critical in regulating the glutamatergic system. While the dopamine pathway is known to be important in the aetiology of schizophrenia, it seems likely that glutamatergic dysfunction can lead to the development of schizophrenia. DTNBP1 is widely expressed in brain, levels are reduced in brains of schizophrenia patients and a DTNBP1 polymorphism has been associated with reduced brain expression. Despite numerous genetic studies no DTNBP1 polymorphism has been strongly implicated in schizophrenia aetiology. Using a haplotype block-based gene-tagging approach we genotyped 13 SNPs in DTNBP1 to investigate possible associations with DTNBP1 and schizophrenia. Four polymorphisms were found to be significantly associated with schizophrenia. The strongest association was found with an A/C SNP in intron 7 (rs9370822). Homozygotes for the C allele of rs9370822 were more than two and a half times as likely to have schizophrenia compared to controls. The other polymorphisms showed much weaker association and are less likely to be biologically significant. These results suggest that DTNBP1 is a good candidate for schizophrenia risk and rs9370822 is either functionally important or in disequilibrium with a functional SNP, although our observations should be viewed with caution until they are independently replicated.
Publisher: BMJ
Date: 25-05-1991
DOI: 10.1136/BMJ.302.6787.1237
Abstract: To assess the effectiveness of a two tier neonatal screening strategy for cystic fibrosis, which combines estimation of immunoreactive trypsinogen followed by direct gene analysis in dried blood spot s les collected at age 5 days. Prospective study of two tier screening strategy. The first tier of testing immunoreactive trypsinogen concentration was measured in dried blood spot s les from neonates aged 4-5 days. In the second tier direct gene analysis to detect cystic fibrosis mutations deltaF508 and deltaI506 was performed in those blood spot s les which produced the highest 1% of immunoreactive trypsinogen values. Direct gene analysis was also performed on blood spot s les from infants with suspected or confirmed meconium ileus, regardless of the immunoreactive trypsinogen value. The South Australian Neonatal Screening Programme, operating from the department of chemical pathology at Adelaide Children's Hospital. Subjects--All 12,056 neonates born in South Australia between December 1989 and June 1990. No selection criteria were applied. All infants found to have two recognised cystic fibrosis mutations on direct gene analysis were referred directly for clinical management, and those with one recognised cystic fibrosis mutation were recalled for a sweat test their families were given genetic counselling. Direct or exclusion of cystic fibrosis by sweat testing of neonates identified as being at high risk of cystic fibrosis on screening and of those at minimum risk but whose subsequent clinical history raised suspicion about the disease. Of the 12,056 infants screened, 11,907 (98.8%) were reported as "cystic fibrosis not indicated" on the basis of low immunoreactive trypsinogen values. Of the 148 (1.23%) infants with raised immunoreactive trypsinogen values and one (0.008%) with meconium ileus, 132 (1.09%) were reported as cystic fibrosis not indicated, four (0.033%) were identified as having cystic fibrosis, and 13 (0.108%) were recalled for sweat testing after direct gene analysis for the presence of the deltaF508 and deltaI506 cystic fibrosis mutations. No cases of affected infants are known to have been missed to date. The strategy of measurement of immunoreactive trypsinogen followed by direct gene analysis is a highly specific neonatal screen for cystic fibrosis, requiring only 2.8 families to be contacted for every case of cystic fibrosis diagnosed.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2014
DOI: 10.1038/TP.2013.111
Abstract: Recent studies suggest that genetic and environmental factors do not account for all the schizophrenia risk, and epigenetics also has a role in disease susceptibility. DNA methylation is a heritable epigenetic modification that can regulate gene expression. Genome-wide DNA methylation analysis was performed on post-mortem human brain tissue from 24 patients with schizophrenia and 24 unaffected controls. DNA methylation was assessed at over 485 000 CpG sites using the Illumina Infinium HumanMethylation450 Bead Chip. After adjusting for age and post-mortem interval, 4641 probes corresponding to 2929 unique genes were found to be differentially methylated. Of those genes, 1291 were located in a CpG island and 817 were in a promoter region. These include NOS1 , AKT1 , DTNBP1 , DNMT1 , PPP3CC and SOX10 , which have previously been associated with schizophrenia. More than 100 of these genes overlap with a previous DNA methylation study of peripheral blood from schizophrenia patients in which 27 000 CpG sites were analysed. Unsupervised clustering analysis of the top 3000 most variable probes revealed two distinct groups with significantly more people with schizophrenia in cluster one compared with controls ( P =1.74 × 10 −4 ). The first cluster composed of 88% of patients with schizophrenia and only 12% controls, whereas the second cluster composed of 27% of patients with schizophrenia and 73% controls. These results strongly suggest that differential DNA methylation is important in schizophrenia etiology and add support for the use of DNA methylation profiles as a future prognostic indicator of schizophrenia.
Publisher: Oxford University Press (OUP)
Date: 1994
DOI: 10.1093/HMG/3.1.207
Publisher: Hindawi Limited
Date: 1992
Abstract: Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI, MPS VI) is an autosomally inherited lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase (EC 3.1.6.1 4-sulfatase). In order to determine the gene defect in a clinically severe MPS VI patient, polymerase chain reaction (PCR) products were generated from the patient's fibroblast mRNA and also from a 4-sulfatase cDNA clone and subjected to the chemical cleavage technique to detect mismatched bases, which were then identified by direct DNA sequencing of the PCR products. The patient was homozygous for an early frameshift mutation caused by the deletion of a G at position 238 (delta G238), which produces a truncated 4-sulfatase with an altered amino acid sequence from amino acid 80 to a premature stop codon at codon 113 relative to the normal 4-sulfatase reading frame of 533 amino acids. Since the mutation occurs only 40 amino acids past the signal peptidase cleavage site, it is most likely that this will result in a protein with no 4-sulfatase activity. This is consistent with the severe clinical presentation and the absence of 4-sulfatase enzyme activity or mutant 4-sulfatase protein in the patient. The patient was also found to be homozygous for two polymorphisms, i.e., a G to A transition at nucleotide 1072 resulting in a valine358 to methionine substitution (V358M) and a salient A to G transition in the third base of the proline397 codon at nucleotide 1191.
Publisher: Springer Science and Business Media LLC
Date: 1991
DOI: 10.1007/BF01213099
Publisher: Frontiers Media SA
Date: 04-12-2014
Publisher: BMJ
Date: 04-06-1994
DOI: 10.1136/BMJ.308.6942.1469
Abstract: To assess the performance and impact of a two tier neonatal screening programme for cystic fibrosis based on an initial estimation of immunoreactive trypsinogen followed by direct gene analysis. Four year prospective study of two tier screening strategy. First tier: immunoreactive trypsinogen measured in dried blood spot s les from neonates aged 3-5 days. Second tier: direct gene analysis of cystic fibrosis mutations (delta F508, delta I506, G551D, G542X, and R553X) in s les with immunoreactive trypsinogen concentrations in highest 1% and in all neonates with meconium ileus or family history of cystic fibrosis. South Australian Neonatal Screening Programme, Adelaide. All 88,752 neonates born in South Australia between December 1989 and December 1993. Neonates with two identifiable mutations were referred directly for clinical assessment and confirmatory sweat test infants with only one identifiable mutation were recalled for sweat test at age 3-4 weeks. Parents of neonates identified as carriers of cystic fibrosis mutation were counselled and offered genetic testing. Identification of all children with cystic fibrosis in the screened population. Of 1004 (1.13%) neonates with immunoreactive trypsinogen > or = 99th centile, 912 (90.8%) had no identifiable mutation. 23 neonates were homozygotes or compound heterozygotes 69 carried one identifiable mutation, of whom six had positive sweat tests. Median age at clinical assessment for the 29 neonates with cystic fibrosis was 3 weeks six had meconium ileus and two had affected siblings. 63 neonates were identified as carriers of a cystic fibrosis mutation. Extra laboratory costs for measuring immunoreactive trypsinogen and direct gene analysis were $A1.50 per neonate screened. This strategy results in early and accurate diagnosis of cystic fibrosis and performs better than screening strategies based on immunoreactive trypsinogen measurement alone.
Publisher: Elsevier BV
Date: 12-1992
Publisher: Cambridge University Press (CUP)
Date: 07-2012
DOI: 10.1016/J.EURPSY.2010.08.004
Abstract: Catechol-O-methyl transferase ( COMT ) encodes an enzyme involved in the metabolism of dopamine and maps to a commonly deleted region that increases schizophrenia risk. A non-synonymous polymorphism (rs4680) in COMT has been previously found to be associated with schizophrenia and results in altered activity levels of COMT . Using a haplotype block-based gene-tagging approach we conducted an association study of seven COMT single nucleotide polymorphisms (SNPs) in 160 patients with a DSM-IV diagnosis of schizophrenia and 250 controls in an Australian population. Two polymorphisms including rs4680 and rs165774 were found to be significantly associated with schizophrenia. The rs4680 results in a Val/Met substitution but the strongest association was shown by the novel SNP, rs165774, which may still be functional even though it is located in intron five. In iduals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. This association was slightly improved when males were analysed separately possibly indicating a degree of sexual dimorphism. Our results confirm that COMT is a good candidate for schizophrenia risk, by replicating the association with rs4680 and identifying a novel SNP association.
Publisher: Oxford University Press (OUP)
Date: 23-02-2010
Publisher: Bentham Science Publishers Ltd.
Date: 09-2008
DOI: 10.2174/157016308785739811
Abstract: Single nucleotide polymorphisms (SNPs) are unique genetic differences between in iduals that contribute in significant ways to the determination of human variation including physical characteristics like height and appearance as well as less obvious traits such as personality, behaviour and disease susceptibility. SNPs can also significantly influence responses to pharmacotherapy and whether drugs will produce adverse reactions. The development of new drugs can be made far cheaper and more rapid by selecting participants in drug trials based on their genetically determined response to drugs. Technology that can rapidly and inexpensively genotype thousands of s les for thousands of SNPs at a time is therefore in high demand. With the completion of the human genome project, about 12 million true SNPs have been identified to date. However, most have not yet been associated with disease susceptibility or drug response. Testing for the appropriate drug response SNPs in a patient requiring treatment would enable in idualised therapy with the right drug and dose administered correctly the first time. Many pharmaceutical companies are also interested in identifying SNPs associated with polygenic traits so novel therapeutic targets can be discovered. This review focuses on technologies that can be used for genotyping known SNPs as well as for the discovery of novel SNPs associated with drug response.
Publisher: Mary Ann Liebert Inc
Date: 08-1992
Abstract: A full-length cDNA clone encoding the lysosomal hydrolase alpha-L-fucosidase was cloned into two retroviral vectors, one using the human cytomegalovirus immediate-early promoter for expression, and the other, the retroviral long terminal repeat (LTR). High-titer hotropic virus was produced for both constructs by infection of PA317 cells, and used to efficiently transduce the alpha-L-fucosidase gene into both human and canine fucosidosis fibroblasts. This resulted in correction of the alpha-L-fucosidase enzyme deficiency characteristic of these fibroblasts. The high levels of recombinant enzyme produced corrected the degradative defect normally seen in these cells, enabling them to catabolize efficiently the accumulated storage product present in lysosomes. Therefore, these retroviral constructs should allow us to start evaluating the value of gene therapy in treating the central nervous system pathology associated with fucosidosis and other lysosomal storage disorders in humans, using a canine model of fucosidosis.
Publisher: OMICS Publishing Group
Date: 2005
Publisher: Informa Healthcare
Date: 22-07-2011
DOI: 10.1185/03007995.2011.603301
Abstract: This commentary critically evaluates the limitations of genetic risk predictions in multifactorial disease, with specific reference to age-related macular degeneration (AMD). AMD is a common blinding disease with 33 million people worldwide experiencing vision impairment. Although gene polymorphism combinations infer an up to 50-fold increased risk of developing the disease, we are far from predicting AMD based on genetics. In the case of complex multifactorial disease such as AMD, to have the same predictive certainty that exists for monogenic disorders, we must account for all gene-environment interactions. We discuss sensitive vision tests that reflect causal gene-environment mechanisms and their potential in AMD risk prediction.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.JANXDIS.2014.09.014
Abstract: Posttraumatic stress disorder (PTSD) is a complex syndrome that occurs following exposure to a potentially life threatening traumatic event. This review summarises the literature on the genetics of PTSD including gene-environment interactions (GxE), epigenetics and genetics of treatment response. Numerous genes have been shown to be associated with PTSD using candidate gene approaches. Genome-wide association studies have been limited due to the large s le size required to reach statistical power. Studies have shown that GxE interactions are important for PTSD susceptibility. Epigenetics plays an important role in PTSD susceptibility and some of the most promising studies show stress and child abuse trigger epigenetic changes. Much of the molecular genetics of PTSD remains to be elucidated. However, it is clear that identifying genetic markers and environmental triggers has the potential to advance early PTSD diagnosis and therapeutic interventions and ultimately ease the personal and financial burden of this debilitating disorder.
Publisher: BMJ
Date: 06-1991
DOI: 10.1136/JMG.28.6.402
Abstract: We report on two adolescent sisters with Sanfilippo syndrome type D with some clinical features different from other cases previously described. They are the oldest cases reported to date and provide new clues about the course of the disease. Enzymatic and immunological characterisation of the patients' fibroblasts indicated deficiency of N-acetylglucosamine-6-sulphate sulphatase (GlcNAc-6S sulphatase). However, Northern blot analysis showed apparently normal mRNA encoding GlcNAc-6S sulphatase. These findings suggest that abnormal translation or premature degradation may be responsible for the enzyme defect in these cases of Sanfilippo syndrome type D.
Publisher: Oxford University Press (OUP)
Date: 1992
DOI: 10.1093/HMG/1.3.195
Abstract: Hunter syndrome or mucopolysaccharidoses type II (MPS-II), is a lysosomal storage disorder caused by a deficiency in the activity of the enzyme iduronate-2-sulphatase (IDS). We have investigated the occurrence of rearrangements and deletions of the IDS gene in a Southern analysis of 46 unrelated MPS-II patients of different ethnic origins using a cDNA clone containing the entire IDS gene as a probe. Structural alterations of the IDS gene were found in DNA from 9 patients two of whom showed large deletions including all coding sequences of the gene. The distal and proximal breakpoint of these deletions were determined by hybridization of markers flanking the IDS gene. Seven of the observed alterations constitute major rearrangements of the gene. Interestingly, six of these rearrangements showed similar or identical patterns by Southern analysis suggestive for a region prone to structural alterations within the IDS gene. We also demonstrate the potential use of the IDS probe for carrier detection in families with a rearranged IDS gene. A contiguous gene deletion syndrome characterized by Hunter syndrome and epilepsy is also discussed.
Publisher: Hindawi Limited
Date: 1994
Abstract: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive genetic disorder caused by deficiency of the lysosomal glycosidase alpha-L-iduronidase. Patients with this disorder present with varied clinical phenotypes ranging from early severe onset of disease and death in early childhood to mild manifestations compatible with adult life. An understanding of the molecular basis of iduronidase deficiency and its correlation to clinical phenotype will improve prognostic prediction at diagnosis, aid in genetic counselling of families, and provide a framework to more accurately assess experimental treatment protocols. We have used the approach of single-strand conformational polymorphism analysis and direct sequencing of the alpha-L-iduronidase gene in an attempt to define the molecular basis of iduronidase deficiency in affected in iduals. An initial series of 19 patients representing 35 independently segregating mutant alleles were studied. In addition to five previously identified mutations (W402X, Q70X, E274X, H82P, and P533R) two novel mutations (A75T and 474-2a-->g) were found. These seven mutations account for 71% of the mutant alleles and 53% of the genotypes in this group of patients. Analysis of a larger independently ascertained group of 103 MPS I patients, mainly of Northern European origin, revealed that together the two novel mutations account for 7% of mutant alleles and are associated with severe clinical phenotypes. These mutations are the most frequent MPS I mutations detected so far after W402X and Q70X. With the definition of these two mutations, a clear picture of the molecular heterogeneity of MPS I is emerging.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2022
DOI: 10.1038/S41380-022-01776-4
Abstract: Posttraumatic stress disorder (PTSD) is a heritable (h
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.JAD.2012.10.013
Abstract: Posttraumatic stress disorder (PTSD) and depressive disorder are over represented in combat veterans. Veterans with both disorders have an increased risk of suicide. The nitric oxide synthase 1 adaptor protein (NOS1AP) gene, which modulates stress-evoked N-methyl-d-aspartate (NMDA) activity, was investigated in combat veterans. A comprehensive genetic analysis of NOS1AP and its association with PTSD was investigated in Vietnam combat veterans with PTSD (n=121) and a group of healthy control in iduals (n=237). PTSD patients were assessed for symptom severity and level of depression using the Mississippi Scale for Combat-Related PTSD and the Beck Depression Inventory-II (BDI). The G allele of NOS1AP SNP rs386231 was significantly associated with PTSD (p=0.002). Analysis of variance revealed significant differences in BDI-II and Mississippi scores between genotypes for rs386231 with the GG genotype associated with increased severity of depression (p=0.002 F=6.839) and higher Mississippi Scale for Combat-Related PTSD scores (p=0.033). Haplotype analysis revealed that the C/G haplotype (rs451275/rs386231) was significantly associated with PTSD (p=0.001). The s le sizes in our study were not sufficient to detect SNP associations with very small effects. In addition the study was limited by its cross sectional design. This is the first study reporting that a variant of the NOS1AP gene is associated with PTSD. Our data also suggest that a genetic variant in NOS1AP may increase the susceptibility to severe depression in patients with PTSD and increased risk for suicide.
Publisher: Springer Science and Business Media LLC
Date: 11-1996
DOI: 10.1038/NG1196-249
Abstract: Striatal adenosine A
Publisher: Elsevier BV
Date: 05-1987
DOI: 10.1016/0006-291X(87)91334-9
Abstract: To improve our understanding of pyruvate carboxylase (PC)(EC 6.4.1.1) structure and the evolution of the biotin-dependent carboxylases we have isolated and sequenced a yeast (Saccharomyces cerevisiae) genomic DNA fragment encoding PC. The identity of the cloned gene was confirmed by comparing the encoded protein with the sequence of a 26 amino acid biotin-containing peptide isolated from yeast PC. The yeast PC sequence is homologous (43% amino acid homology) to the rat PC sequence, although the carboxyl-terminus was found to be 44 residues from the biotinyl-lysine whereas in all biotin carboxylases sequenced to date the biotin is 35 residues from the carboxyl-terminus.
Publisher: Hindawi Limited
Date: 1994
Abstract: Metachromatic leukodystrophy is an autosomal recessive inherited lysosomal storage disease. It can be caused by mutations in two different genes, the arylsulfatase A and the prosaposin gene. These genes encode two proteins that are needed for the proper degradation of cerebroside sulfate, a glycolipid mainly found in the myelin membranes. Deficiency of arylsulfatase A or of a proteolytic product of prosaposin leads to the accumulation of cerebroside sulfate, which causes a lethal progressive demyelination. Mutations in the arylsulfatase A gene are far more frequent than those of the prosaposin gene. So far 31 amino acid substitutions, one nonsense mutation, three small deletions, three splice donor site mutations, and one combined missense/splice donor site mutation have been identified in the arylsulfatase A gene. Two of these mutant alleles are frequent, accounting for about one-half of all mutant alleles, whereas the remainder are heterogeneous. Amino acid substitutions cluster in exons 2 and 3, a region that shows a high degree of conservation among sulfatases of different function and origin. Different mutations are associated with phenotypes of different severity, but there is a remarkable variability of severity when patients with identical genotypes are compared. Demonstration of an arylsulfatase A deficiency is not a proof of metachromatic leukodystrophy, since a substantial deficiency without any clinical consequences is frequent in the general population. This deficiency is caused by an arylsulfatase A allele, which due to certain mutations encodes greatly reduced amounts of functional enzyme. However, these amounts are sufficient to sustain a normal phenotype. In the diagnosis and genetic counseling, these deficiencies must be differentiated from those causing metachromatic leukodystrophy. So far only six patients with mutations in the prosaposin gene have been described, in which three defective alleles two with amino acid substitutions and one with a 33-bp insertion have been identified.
Publisher: Elsevier BV
Date: 10-1987
DOI: 10.1016/0003-9861(87)90343-2
Abstract: Pyruvate carboxylase deficiency was previously reported to be the biochemical lesion in a yeast mutant, designated pyc, which cannot utilize ethanol, acetate, pyruvate, aspartate, or oxaloacetate as the sole carbon source [C. Wills and T. Melham (1985) Arch. Biochem. Biophys. 236, 782-791 C. Wills et al. (1986) Arch. Biochem. Biophys. 246, 306-320]. We present evidence here that the level of pyruvate carboxylase activity as well as the native and subunit molecular weights of this enzyme are identical in the mutant and the wild type. In addition we have used immunocytochemical labeling to demonstrate the exclusively cytosolic localization of this enzyme in both the mutant and wild-type yeast.
Publisher: Springer Science and Business Media LLC
Date: 07-1991
DOI: 10.1007/BF01233067
Abstract: This discussion paper reviews the health impacts, physical and mental, of domestic violence and explores the link between domestic violence and psychological symptoms. This paper focuses more on posttraumatic stress disorder (PTSD) than depression and low self-esteem because doctors are less familiar with PTSD. The barriers preventing health workers from detecting domestic violence are reviewed and the fear of health professionals that asking about trauma can harm patients is explored. The article then outlines practical strategies to improve detection of domestic violence using patients' presenting psychological symptoms and the diagnoses frequently associated with domestic violence namely, PTSD, depression and low self-esteem. It is argued that it is inadvisable to try to implement a policy of screening for domestic violence in general practice when the public health model is currently inappropriate. The paper discusses why the diagnostic frameworks of depression and PTSD are helpful in general practice, not only in detecting domestic violence but in working with the patient to establish trust and ways forward that can be tailored to meet the needs of the patient and their children. Patients' and professionals' dilemmas about what to do once domestic violence is detected are briefly explored.
Publisher: Elsevier BV
Date: 11-1988
DOI: 10.1016/S0006-291X(88)80035-4
Abstract: Glucosamine-6-sulfatase is a lysosomal enzyme which degrades glycosaminoglycans and is deficient in mucopolysaccharidosis type IIID. Human liver contains two major active forms of glucosamine-6-sulfatase, form A which has a single 78 kDa polypeptide and form B which has two polypeptides of 48 kDa and 32 kDa. A 1761 base pair cDNA clone encoding the complete 48 kDa polypeptide of form B was isolated. Form A is shown to be processed to form B with the 48 kDa polypeptide C-terminal to the 32 kDa polypeptide, and it is shown that C-terminal processing is limited to a region of thirty amino acids. The glucosamine-6-sulfatase sequence reveals homology with steroid sulfatase, a microsomal enzyme.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.JPSYCHIRES.2010.09.014
Abstract: Previous studies yielded evidence for dysbindin (DTNBP1) to impact the pathogenesis of schizophrenia on the one hand and affective disorders such as bipolar or major depressive disorder (MDD) on the other. Thus, in the present study we investigated whether DTNBP1 variation was associated with psychotic depression as a severe clinical manifestation of MDD possibly constituting an overlapping phenotype between affective disorders and schizophrenia. A s le of 243 Caucasian inpatients with MDD (SCID-I) was genotyped for 12 SNPs spanning 92% of the DTNBP1 gene region. Differences in DTNBP1 genotype distributions across diagnostic subgroups of psychotic (N = 131) vs. non-psychotic depression were estimated by Pearson Chi(2) test and logistic regression analyses adjusted for age, gender, Beck Depression Inventory (BDI) and the Global Assessment of Functioning Scale (GAF). Overall, patients with psychotic depression presented with higher BDI and lower GAF scores expressing a higher severity of the illness as compared to depressed patients without psychotic features. Four DTNBP1 SNPs, particularly rs1997679 and rs9370822, and the corresponding haplotypes, respectively, were found to be significantly associated with the risk of psychotic depression in an allele-dose fashion. In summary, the present results provide preliminary support for dysbindin (DTNBP1) gene variation, particularly SNPs rs1997679 and rs9370822, to be associated with the clinical phenotype of psychotic depression suggesting a possible neurobiological mechanism for an intermediate trait on the continuum between affective disorders and schizophrenia.
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.BBRC.2007.07.191
Abstract: It is known that fatty acids (FAs) regulate transcription through a number of FA responsive transcription factors. In order to investigate the effect of FAs on gene regulation in cultured human hepatocytes we examined the effect of palmitate on hepatic glucokinase (GK) promoter activity and expression of transcription factors that regulate GK expression. GK promoter activity was increased in constructs lacking a cAMP response element (CRE), while palmitate incubation decreased GK promoter activity in CRE-negative constructs. Cells exposed to palmitate showed increased levels of PPARalpha apolipoprotein-AII and -B100 mRNA and decreased levels of SREBP-1c mRNA but there was no effect on LXRalpha and HNF-4alpha mRNA. In addition, cDNA microarray analysis of short-term (1.5h) transcriptional regulation by palmitate, oleate, and eicosapentaenoic acid (EPA) identified that oleate and EPA initiated similar changes in the pattern of hepatic gene regulation, whereas palmitate had little effect.
Publisher: Elsevier BV
Date: 08-1994
Abstract: Deficiency of the lysosomal enzyme, N-acetylgalactosamine 6-sulfatase (GALNS EC 3.1.6.4), results in the storage of the glycosaminoglycans, keratan sulfate and chondroitin 6-sulfate, which leads to the lysosomal storage disorder Morquio A syndrome. Four overlapping genomic clones derived from a chromosome 16-specific gridded cosmid library containing the entire GALNS gene were isolated. The structure of the gene and the sequence of the exon/intron boundaries and the 5' promoter region were determined. The GALNS gene is split into 14 exons spanning approximately 40 kb. The potential promoter for GALNS lacks a TATA box but contains GC box consensus sequences, consistent with its role as a housekeeping gene. The GALNS gene contains an Alu repeat in intron 5 and a VNTR-like sequence in intron 6.
Publisher: Elsevier BV
Date: 05-2010
Publisher: Oxford University Press (OUP)
Date: 27-11-2007
Abstract: The proximal promoter of the kallikrein-related peptidase 3 gene (KLK3/PSA) contains a single-nucleotide polymorphism (G-158A) located within the second canonical half-site for the prostate-specific antigen (PSA) androgen response element 1 (AREI). Previous studies suggest that this polymorphism may be associated with higher PSA levels and increase prostate cancer risk. We have investigated the potential functional significance of this polymorphism and its association with prostate cancer susceptibility by genotyping the G-158A polymorphism in 209 men diagnosed with prostate cancer and 223 healthy control men in an Australian Caucasian population. Functional analyses of PSA AREI demonstrated that the A allele increased binding of AREI to the androgen receptor, as well as increasing transcriptional response to androgens. Association studies of the G-158A polymorphism demonstrated that men with an A/A genotype had a 3-fold increased risk for developing prostate cancer [95% confidence intervals (CIs) = 1.36-6.52] and men with an A/G genotype had a 2.4-fold increased risk (95% CIs = 1.23-4.81). Under a dominant model, the A allele conferred a 2.6-fold increased risk for prostate cancer (95% CIs = 1.37-4.96, P = 0.004). Taken together with the finding that the G-158A polymorphism is associated with an increased risk of prostate cancer in Australian men, our functional data suggest that the presence of the A allele in AREI may, in part, account for the altered PSA regulation seen in prostate cancer.
Publisher: Public Library of Science (PLoS)
Date: 19-02-2014
No related grants have been discovered for Phillip Morris.