ORCID Profile
0000-0003-0636-4836
Current Organisation
Neuroscience Research Australia
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Publisher: CMA Joule Inc.
Date: 17-03-2021
DOI: 10.1503/JPN.200083
Abstract: Background: Bipolar disorder is a highly heritable psychiatric condition for which specific genetic factors remain largely unknown. In the present study, we used combined whole-exome sequencing and linkage analysis to identify risk loci and dissect the contribution of common and rare variants in families with a high density of illness. Methods: Overall, 117 participants from 15 Australian extended families with bipolar disorder (72 with affective disorder, including 50 with bipolar disorder type I or II, 13 with schizoaffective disorder–manic type and 9 with recurrent unipolar disorder) underwent whole-exome sequencing. We performed genome-wide linkage analysis using MERLIN and conditional linkage analysis using LAMP. We assessed the contribution of potentially functional rare variants using a genebased segregation test. Results: We identified a significant linkage peak on chromosome 10q11-q21 (maximal single nucleotide polymorphism = rs10761725 exponential logarithm of the odds [LODexp] = 3.03 empirical p = 0.046). The linkage interval spanned 36 protein-coding genes, including a gene associated with bipolar disorder, ankyrin 3 (ANK3). Conditional linkage analysis showed that common ANK3 risk variants previously identified in genome-wide association studies — or variants in linkage disequilibrium with those variants — did not explain the linkage signal (rs10994397 LOD = 0.63 rs9804190 LOD = 0.04). A family-based segregation test with 34 rare variants from 14 genes under the linkage interval suggested rare variant contributions of 3 brain-expressed genes: NRBF2 (p = 0.005), PCDH15 (p = 0.002) and ANK3 (p = 0.014). Limitations: We did not examine non-coding variants, but they may explain the remaining linkage signal. Conclusion: Combining family-based linkage analysis with next-generation sequencing data is effective for identifying putative disease genes and specific risk variants in complex disorders. We identified rare missense variants in ANK3, PCDH15 and NRBF2 that could confer disease risk, providing valuable targets for functional characterization.
Publisher: Wiley
Date: 11-2002
DOI: 10.1111/J.1751-0813.2002.TB11301.X
Abstract: To develop a routine procedure for establishing the inherited congenital myoclonus (ICM) genotype of cattle and to obtain an estimate of the prevalence of heterozygotes for ICM and maple syrup urine disease (MSUD) in Australian Poll Herefords. A mismatch lification procedure was developed to genotype for ICM. The ICM and MSUD genotypes of subjects from a 'neuraxial oedema' experimental breeding herd were investigated. Tail hair roots were used as a source of target DNA to determine the ICM and MSUD genotypes of 455 Poll Hereford bulls. An Acc I mismatch procedure was found to be suitable to genotype cattle for the ICM alleles using tail hair roots as the source of DNA. Based on the prevalence of heterozygotes among saleyard and sale bulls in the early 1990s, and contemporary slaughter bulls, the frequencies of the alleles responsible for ICM and MSUD were estimated to be between 0.01 and 0.02. This survey demonstrates that the mutations responsible for ICM and MSUD are present in the Australian Poll Hereford population. PCR tests could be used to advantage in differential diagnosis of neurological disease in newly born calves and in selection of Poll Hereford seed stock.
Publisher: Frontiers Media SA
Date: 17-05-2016
Publisher: EJournal Publishing
Date: 10-2019
Publisher: Springer Science and Business Media LLC
Date: 08-08-2015
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.BIOPSYCH.2010.03.016
Abstract: This study was intended to assess the extent to which the low-expression alleles of the serotonin transporter gene promoter predict poor response to cognitive behavior therapy in patients with posttraumatic stress disorder (PTSD). Forty-five patients with PTSD underwent an 8-week exposure-based cognitive behavior therapy program and provided mouth swabs or saliva s les to extract genomic DNA and classify in iduals according to four allelic forms (S(A), S(G), L(A), L(G)) of the 5-HTT-linked polymorphic region (5-HTTLPR). We determined whether the 5-HTTLPR genotype predicted change in PTSD severity following treatment (n = 45) and 6 months later (n = 42). After controlling for pretreatment PTSD severity and number of treatment sessions, the 5-HTTLPR low-expression genotype group (S or L(G) allele carriers) displayed more severe PTSD 6 months following treatment relative to other patients. This study suggests a genetic contribution to treatment outcome following cognitive behavior therapy and implicates the serotonergic system in response to exposure-based treatments in PTSD.
Publisher: Springer Science and Business Media LLC
Date: 10-03-2013
Publisher: Elsevier BV
Date: 08-1992
DOI: 10.1016/S0006-291X(05)81462-7
Abstract: A novel receptor cDNA was isolated from a human hippoc al cDNA library. The encoded polypeptide contains structural features consistent with its classification as a G protein-coupled receptor and shares 45% homology with the human A1 and A2a adenosine receptors. Chinese hamster ovary K1 cells expressing this receptor showed marked stimulation of adenylate cyclase when treated with 1mM adenosine. There was no response to ligands selective for A1 and A2a receptors but the general adenosine agonist N-ethylcarboxyamidoadenosine (NECA) caused a 10 fold increase in cyclic AMP accumulation with an EC50 of approximately 0.9 microM. This effect was inhibited by the adenosine receptor antagonist theophylline. Specific binding of A1 and A2a selective agonists and NECA was not detected. It is proposed that the novel receptor is a human brain adenosine A2b receptor subtype.
Publisher: Informa UK Limited
Date: 17-10-2013
Publisher: Wiley
Date: 07-2002
DOI: 10.1002/MDS.10216
Publisher: Rockefeller University Press
Date: 15-04-2002
DOI: 10.1085/JGP.20028552
Abstract: Ligand-gated ion channel receptors mediate neuronal inhibition or excitation depending on their ion charge selectivity. An investigation into the determinants of ion charge selectivity of the anion-selective α1 homomeric glycine receptor (α1 glycine receptor [GlyR]) was undertaken using point mutations to residues lining the extra- and intracellular ends of the ion channel. Five mutant GlyRs were studied. A single substitution at the intracellular mouth of the channel (A-1′E GlyR) was sufficient to convert the channels to select cations over anions with PCl/PNa = 0.34. This result delimits the selectivity filter and provides evidence that electrostatic interactions between permeating ions and pore residues are a critical factor in ion charge selectivity. The P-2′Δ mutant GlyR retained its anion selectivity (PCl/PNa = 3.81), but it was much reduced compared with the wild-type (WT) GlyR (PCl/PNa = 27.9). When the A-1′E and the P-2′Δ mutations were combined (selectivity double mutant [SDM] GlyR), the relative cation permeability was enhanced (PCl/PNa = 0.13). The SDM GlyR was also Ca2+ permeable (PCa/PNa = 0.29). Neutralizing the extracellular mouth of the SDM GlyR ion channel (SDM+R19′A GlyR) produced a more Ca2+-permeable channel (PCa/PNa = 0.73), without drastically altering monovalent charge selectivity (PCl/PNa = 0.23). The SDM+R19′E GlyR, which introduces a negatively charged ring at the extracellular mouth of the channel, further enhanced Ca2+ permeability (PCa/PNa = 0.92), with little effect on monovalent selectivity (PCl/PNa = 0.19). Estimates of the minimum pore diameter of the A-1′E, SDM, SDM+R19′A, and SDM+R19′E GlyRs revealed that these pores are larger than the α1 GlyR, with the SDM-based GlyRs being comparable in diameter to the cation-selective nicotinic acetylcholine receptors. This result provides evidence that the diameter of the ion channel is also an important factor in ion charge selectivity.
Publisher: Springer Science and Business Media LLC
Date: 06-2005
DOI: 10.1007/S00249-005-0479-7
Abstract: Dequalinium has recently been reported to block CNGA1 and CNGA2 channels expressed in Xenopus laevis. Using the inside-out configuration of the patch-cl technique, we examined the effects of dequalinium on rat olfactory CNGA2 channels expressed in human embryonic kidney (HEK293) cells and studied aspects of its molecular mechanism of action. We found that cytoplasmic dequalinium blocked wild-type (WT) CNGA2 channels in a voltage-dependent manner with an IC(50) of approximately 1.3 muM at a V(m) of + 60 mV, and an effective fractional charge, zdelta, of +0.8 (z=2, delta=+0.4), suggesting that cytoplasmic dequalinium interacts with a binding site that is about two fifths of the way along the membrane electric field (from the intracellular side). Neutralizing the negatively charged pore lining glutamate acid residue (E342Q) still allows effective channel block by cytoplasmic dequalinium with an IC(50) of approximately 2.2 muM at a V(m) of +60 mV but now having a zdelta of +0.1 (delta=+0.05), indicating a profoundly decreased level of voltage-dependence. In addition, by comparing the extent of block under different levels of channel activation, we show that the block by cytoplasmic dequalinium displayed clear state-dependence in WT channels by interacting predominantly with the closed channel, whereas the block in E342Q channels was state-independent. Application of dequalinium to the external membrane surface also blocked currents through WT channels and the E342Q mutation significantly increased the IC(50) for external block approximately fivefold. These results confirm dequalinium as a potent, voltage-dependent and state-dependent blocker of cyclic-nucleotide-gated channels, and show that neutralization of the E342 residue profoundly affects the block by both cytoplasmic and external application of dequalinium.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Public Library of Science (PLoS)
Date: 26-12-2018
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.PSYCHRES.2012.07.008
Abstract: Investigations into serotonin transporter and anxiety and depression have shown an association between stress, depression onset and genotype. We investigated the relationship between 5-HTTLPR genotype and depression and anxiety in a population with diabetes mellitus, a condition associated with high rates of stress and depression. Participants were classified according to 'S' and 'L' alleles as well as the modification of the single nucleotide polymorphism (SNP) rs25531. The 5-HTTLPR low-expression genotype group (S or L(G) allele carriers) had significantly higher psychological distress (K10) scores (N=234, P=0.047). Subsequent analysis revealed that the effect of genotype was related to anxiety symptoms rather than depression symptoms. Furthermore, the main effect of genotype was not observed when the modification of the SNP polymorphism was not taken into account. Findings suggest that 5-HTTLPR/rs25531 genotype is associated with psychological distress in a s le of subjects with diabetes.
Publisher: Rockefeller University Press
Date: 13-03-2006
Abstract: Cyclic nucleotide-gated (CNG) channels play a critical role in olfactory and visual transduction. Site-directed mutagenesis and inside-out patch-cl recordings were used to investigate ion permeation and selectivity in two mutant homomeric rat olfactory CNGA2 channels expressed in HEK293 cells. A single point mutation of the negatively charged pore loop (P-loop) glutamate (E342) to either a positively charged lysine or arginine resulted in functional channels, which consistently responded to cGMP, although the currents were generally extremely small. The concentration–response curve of the lysine mutant channel was very similar to that of wild-type (WT) channels, suggesting no major structural alteration to the mutant channels. Reversal potential measurements, during cytoplasmic NaCl dilutions, showed that the lysine and the arginine mutations switched the selectivity of the channel from cations (PCl/PNa = 0.07 [WT]) to anions (PCl/PNa = 14 [Lys] or 10 [Arg]). Relative anion permeability sequences for the two mutant channels, measured with bi-ionic substitutions, were NO3− & I− & Br− & Cl− & F− & acetate−, the same as those obtained for anion-selective GABA and glycine channels. The mutant channels also seem to have an extremely small single-channel conductance, measured using noise analysis of about 1–2 pS, compared to a WT value of about 29 pS. The results showed that it is predominantly the charge of the E342 residue in the P-loop, rather than the pore helix dipoles, which controls the cation–anion selectivity of this channel. However, the outward rectification displayed by both mutant channels in symmetrical NaCl solutions suggests that the negative ends of the pore helix dipoles may play a role in reducing the outward movement of Cl− ions through these anion-selective channels. These results have potential implications for the determinants of anion–cation selectivity in the large family of P-loop–containing channels.
Publisher: Emerald
Date: 17-06-2021
DOI: 10.1108/JFMM-07-2020-0148
Abstract: The purpose of this research is to investigate the status of sustainable development and corporate social responsibility in fashion enterprises in Vietnam. This paper is qualitative in nature and utilized a multiple case study approach (questionnaires and face-to-face interviews) to achieve the objectives of the research. NVivo was used to analyze the data. Findings showed that by collaborating with the local artisans to create the unique clothing lines, the fashion brands try to blend and upscale the traditional indigenous clothing styles with modern design concepts to promote the ersity of Vietnamese ethnic culture. The findings also suggest that both the small and medium-sized enterprises (SMEs) and large enterprises (LEs) should maintain their corporate social responsibility (CSR) concepts to comply with the legal obligations such as salary and welfare benefits for employees, work safety, gender equality and promotions. Further, the CSR activities should address the social issues with their target stakeholders, particularly with the local communities. This study sought to provide a snapshot on the current sustainable practices followed in Vietnamese fashion enterprises.
Publisher: Springer Science and Business Media LLC
Date: 07-2014
Publisher: Springer Science and Business Media LLC
Date: 13-03-2018
DOI: 10.1038/S41398-018-0113-Y
Abstract: Bipolar disorder (BD) is a complex psychiatric condition with high heritability, the genetic architecture of which likely comprises both common variants of small effect and rare variants of higher penetrance, the latter of which are largely unknown. Extended families with high density of illness provide an opportunity to map novel risk genes or consolidate evidence for existing candidates, by identifying genes carrying pathogenic rare variants. We performed whole-exome sequencing (WES) in 15 BD families (117 subjects, of whom 72 were affected), augmented with copy number variant (CNV) microarray data, to examine contributions of multiple classes of rare genetic variants within a familial context. Linkage analysis and haplotype reconstruction using WES-derived genotypes enabled exclusion of false-positive single-nucleotide variants (SNVs), CNV inheritance estimation, de novo variant identification and candidate gene prioritization. We found that rare predicted pathogenic variants shared among ≥3 affected relatives were overrepresented in postsynaptic density (PSD) genes ( P = 0.002), with no enrichment in unaffected relatives. Genome-wide burden of likely gene-disruptive variants was no different in affected vs. unaffected relatives ( P = 0.24), but correlated significantly with age of onset ( P = 0.017), suggesting that a high disruptive variant burden may expedite symptom onset. The number of de novo variants was no different in affected vs. unaffected offspring ( P = 0.89). We observed heterogeneity within and between families, with the most likely genetic model involving alleles of modest effect and reduced penetrance: a possible exception being a truncating X-linked mutation in IRS4 within a family-specific linkage peak. Genetic approaches combining WES, CNV and linkage analyses in extended families are promising strategies for gene discovery.
Publisher: Wiley
Date: 1997
Publisher: Springer Science and Business Media LLC
Date: 20-01-2013
Publisher: Springer Science and Business Media LLC
Date: 03-08-2022
DOI: 10.1038/S41398-022-02079-6
Abstract: Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk for BD in young people at high familial risk (HR) of BD. Peripheral blood-derived DNA was assayed using Illumina PsychArray, and Methylation-450K or -EPIC BeadChips. Polygenic risk scores (PRS) were calculated using summary statistics from recent genome-wide association studies for BD, major depressive disorder (MDD) and cross-disorder (meta-analysis of eight psychiatric disorders). Unrelated HR participants of European ancestry ( n = 103) were stratified based on their BD-PRS score within the HR-population distribution, and the top two quintiles (High-BD-PRS n = 41) compared against the bottom two quintiles (Low-BD-PRS n = 41). The High-BD-PRS stratum also had higher mean cross-disorder-PRS and MDD-PRS (ANCOVA p = 0.035 and p = 0.024, respectively). We evaluated DNA methylation differences between High-BD-PRS and Low-BD-PRS strata using linear models. One differentially methylated probe (DMP) (cg00933603 p = 3.54 × 10 −7 ) in VARS2 , a mitochondrial aminoacyl-tRNA synthetase, remained significantly hypomethylated after multiple-testing correction. Overall, BD-PRS appeared to broadly impact epigenetic processes, with 1,183 genes mapped to nominal DMPs ( p 0.05) these displayed convergence with genes previously associated with BD, schizophrenia, chronotype, and risk taking. We tested poly-methylomic epigenetic profiles derived from nominal DMPs in two independent s les ( n = 54 and n = 82, respectively), and conducted an exploratory evaluation of the effects of family environment, indexing cohesion and flexibility. This study highlights an important interplay between heritable risk and epigenetic factors, which warrant further exploration.
Publisher: Elsevier BV
Date: 09-1992
DOI: 10.1016/0169-328X(92)90152-2
Abstract: A cDNA encoding a G protein-coupled receptor of unknown ligand specificity was isolated from a human hippoc al cDNA library by virtue of the high degree of structural homology between members of this receptor family. The cloned receptor DNA was transfected into human embryonic kidney 293 cells. Stably transfected cell lines bound a variety of adenosine agonists and antagonists with affinities characteristic of a brain adenosine A2a receptor. The A2a specific agonist CGS21680 stimulated cAMP production but did not alter intracellular calcium concentrations in transfected 293 cells.
Publisher: Elsevier BV
Date: 02-2001
Publisher: Elsevier BV
Date: 06-2017
Publisher: Elsevier BV
Date: 1995
DOI: 10.1016/0896-6273(95)90251-1
Abstract: Agonist binding to the inhibitory glycine receptor (GlyR) initiates the opening of a chloride-selective channel that modulates the neuronal membrane potential. Point mutations of the GlyR, substituting Arg-271 with either Leu or Gln, have been shown to underlie the inherited neurological disorder startle disease (hyperekplexia). We show that these substitutions result in the redistribution of GlyR single-channel conductances to lower conductance levels. Additionally, the binding of the glycinergic agonists beta-alanine and taurine to mutated GlyRs does not initiate a chloride current, but instead competitively antagonizes currents activated by glycine. These findings are consistent with mutations of Arg-271 resulting in the uncoupling of the agonist binding process from the channel activation mechanism of the receptor.
Publisher: Elsevier BV
Date: 12-2003
Publisher: Elsevier BV
Date: 2016
Publisher: Cold Spring Harbor Laboratory
Date: 06-07-2018
DOI: 10.1101/363846
Abstract: The contactin-associated protein-like 2 (CNTNAP2) gene is a member of the neurexin superfamily. CNTNAP2 was implicated in the cortical dysplasia-focal epilepsy (CDFE) syndrome, a recessive disease characterized by intellectual disability, epilepsy, language impairments and autistic features. Associated SNPs and heterozygous deletions in CNTNAP2 have also frequently been reported in autism, schizophrenia and other psychiatric or neurological disorders. We aim here to gain conclusive evidence for the role of CNTNAP2 in susceptibility to psychiatric disorders by the comprehensive analysis of large genomic datasets. In this study we used: i) summary statistics from the Psychiatric Genomics Consortium (PGC) GWAS ii) examined all reported CNTNAP2 structural variants in patients and controls iii) performed cross-disorder analysis of functional or previously associated SNPs iv) and conducted burden tests for pathogenic rare variants using sequencing data (4,483 ASD and 6,135 schizophrenia cases, and 13,042 controls). In a CNV mircroarray study, we previously identified a 131kb deletion in CNTNAP2 intron 1, removing a FOXP2 transcription factor binding site in an extended BD family. Here we perform a quantitative-PCR validation showing imperfect segregation with disease (5 bipolar disorder relatives). The distribution of CNVs across CNTNAP2 in psychiatric cases from previous reports was no different from controls of the database of genomic variants. Gene-based association testing did not implicate common variants in autism, schizophrenia or other psychiatric phenotypes. The association of proposed functional SNPs rs7794745 and rs2710102, reported to influence brain connectivity, was not replicated nor did functional SNPs yield significant results in meta-analysis across psychiatric disorders. Disrupting CNTNAP2 rare variant burden was not higher in autism or schizophrenia compared to controls. This large comprehensive candidate gene study indicates that CNTNAP2 may not be a robust risk gene for psychiatric phenotypes. Genetic mutations that disrupt both copies of the CNTNAP2 gene lead to severe disease, characterized by profound intellectual disability, epilepsy, language difficulties and autistic traits. Researchers hypothesized that this gene may also be involved in autism given some overlapping clinical features with this disease. Indeed, several large DNA deletions affecting one of the two copies of CNTNAP2 were found in some patients with autism, and later also in patients with schizophrenia, bipolar disorder, ADHD and epilepsy, suggesting that this gene was involved in several psychiatric or neurologic diseases. Other studies considered genetic sequence variations that are common in the general population, and suggested that two such sequence variations in CNTNAP2 predispose to psychiatric diseases by influencing the functionality and connectivity of the brain. In the current study, we report the deletion of one copy of CNTNAP2 in a patient with bipolar disorder from an extended family where five relatives were affected with this condition. To better understand the involvement of CNTNAP2 in risk of mental illness, we performed several genetic analyses using a series of large publically available or in-house datasets, comprising many thousands of patients and controls. Despite the previous consideration of CNTNAP2 as a strong candidate gene for autism or schizophrenia, we show that neither common, deletion nor ultra-rare variants in CNTNAP2 are likely to play a major role in risk of psychiatric diseases.
Publisher: Wiley
Date: 16-08-2004
Publisher: Portland Press Ltd.
Date: 15-12-1987
DOI: 10.1042/BJ2480937
Abstract: A plasmid, termed pTacGST2, which contains the complete coding sequence of a GST2 (glutathione S-transferase 2) subunit and permits the expression of the protein in Escherichia coli was constructed. The expressed protein had the same subunit Mr as the enzyme from normal human liver and retained its catalytic function with both GST and glutathione peroxidase activity. Antiserum raised against the bacterially synthesized protein cross-reacted with all the basic GST isoenzymes in human liver. The electrophoretic mobility in agarose of the bacterially expressed isoenzyme suggested that its pI is identical with that of the cationic isoenzyme from human liver previously termed GST2 type 1. The available evidence suggests that the three common cationic isoenzymes found in human liver are the products of two very similar gene loci.
No related grants have been discovered for Kerrie Pierce.