ORCID Profile
0000-0001-9298-3072
Current Organisations
University of Adelaide Robinson Institute
,
University of Adelaide
,
University of Sydney
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Publisher: Springer Science and Business Media LLC
Date: 23-12-2010
Publisher: Elsevier BV
Date: 02-2008
Publisher: Wiley
Date: 06-05-2013
DOI: 10.1002/AJMG.A.35922
Publisher: BMJ
Date: 04-2016
Publisher: Elsevier BV
Date: 09-2010
Publisher: Springer Science and Business Media LLC
Date: 16-03-2202
Publisher: Elsevier BV
Date: 03-2020
Publisher: Oxford University Press (OUP)
Date: 28-07-2006
DOI: 10.1093/HMG/DDL186
Publisher: Wiley
Date: 11-05-2018
DOI: 10.1111/EPI.14087
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1038/S41467-019-12671-Y
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7 . The ATTTC expansions segregate in 158/158 in iduals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.
Publisher: Springer Science and Business Media LLC
Date: 07-2016
DOI: 10.1007/S00439-016-1700-8
Abstract: Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder characterized by adult onset, involuntary muscle jerks, cortical myoclonus and occasional seizures. FAME is genetically heterogeneous with more than 70 families reported worldwide and five potential disease loci. The efforts to identify potential causal variants have been unsuccessful in all but three families. To date, linkage analysis has been the main approach to find and narrow FAME critical regions. We propose an alternative method, pedigree free identity-by-descent (IBD) mapping, that infers regions of the genome between in iduals that have been inherited from a common ancestor. IBD mapping provides an alternative to linkage analysis in the presence of allelic and locus heterogeneity by detecting clusters of in iduals who share a common allele. Succeeding IBD mapping, gene prioritization based on gene co-expression analysis can be used to identify the most promising candidate genes. We performed an IBD analysis using high-density single nucleotide polymorphism (SNP) array data followed by gene prioritization on a FAME cohort of ten European families and one Australian/New Zealander family eight of which had known disease loci. By identifying IBD regions common to multiple families, we were able to narrow the FAME2 locus to a 9.78 megabase interval within 2p11.2-q11.2. We provide additional evidence of a founder effect in four Italian families and allelic heterogeneity with at least four distinct founders responsible for FAME at the FAME2 locus. In addition, we suggest candidate disease genes using gene prioritization based on gene co-expression analysis.
Publisher: MDPI AG
Date: 31-07-2023
Abstract: Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development.
Publisher: Springer Science and Business Media LLC
Date: 09-12-2020
DOI: 10.1038/S41525-020-00162-9
Abstract: USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X -female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X -female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X -female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X -female syndrome, and highlights major differences when compared to USP9X -male associated neurodevelopmental disorders.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-06-2016
Publisher: Hindawi Limited
Date: 30-09-2015
DOI: 10.1002/HUMU.22901
Publisher: Wiley
Date: 22-01-2023
DOI: 10.1111/EPI.17504
Abstract: Familial adult myoclonus epilepsy (FAME) results from the same pathogenic TTTTA/TTTCA pentanucleotide repeat expansion in six distinct genes encoding proteins with different subcellular localizations and very different functions, which poses the issue of what causes the neurobiological disturbances that lead to the clinical phenotype. Postmortem and electrophysiological studies have pointed to cortical hyperexcitability as well as dysfunction and neurodegeneration of both the cortex and cerebellum of FAME subjects. FAME expansions, contrary to the same expansion in DAB1 causing spinocerebellar ataxia type 37, seem to have no or limited impact on their recipient gene expression, which suggests a pathophysiological mechanism independent of the gene and its function. Current hypotheses include toxicity of the RNA molecules carrying UUUCA repeats, or toxicity of polypeptides encoded by the repeats, a mechanism known as repeat‐associated non‐AUG translation. The analysis of postmortem brains of FAME1 expansion (in SAMD12 ) carriers has revealed the presence of RNA foci that could be formed by the aggregation of RNA molecules with abnormal UUUCA repeats, but evidence is still lacking for other FAME subtypes. Even when the expansion is located in a gene ubiquitously expressed, expression of repeats remains undetectable in peripheral tissues (blood, skin). Therefore, the development of appropriate cellular models (induced pluripotent stem cell‐derived neurons) or the study of affected tissues in patients is required to elucidate how FAME repeat expansions located in unrelated genes lead to disease.
Publisher: Oxford University Press (OUP)
Date: 06-10-2015
DOI: 10.1093/HMG/DDV414
Abstract: Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected in iduals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected in iduals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.
Publisher: SAGE Publications
Date: 09-04-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-05-2021
DOI: 10.1212/WNL.0000000000011855
Abstract: To identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients. We performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing data from 1,165 patients with epilepsy from the Epi4K dataset and 1,329 Australian patients with epilepsy from the Epi25 dataset were interrogated. Targeted resequencing was performed on 278 patients with febrile seizures or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing. Eight previously unreported missense variants were identified in SLC32A1 , coding for the vesicular inhibitory amino acid cotransporter VGAT. Two variants cosegregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected in iduals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE). Missense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype–phenotype spectrum associated with SLC32A1 variants.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2021
DOI: 10.1038/S41525-021-00238-0
Abstract: Cerebral palsy (CP) is the most common cause of childhood physical disability, with incidence between 1/500 and 1/700 births in the developed world. Despite increasing evidence for a major contribution of genetics to CP aetiology, genetic testing is currently not performed systematically. We assessed the diagnostic rate of genome sequencing (GS) in a clinically unselected cohort of 150 singleton CP patients, with CP confirmed at years of age. Clinical grade GS was performed on the proband and variants were filtered, and classified according to American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Variants classified as pathogenic or likely pathogenic (P/LP) were further assessed for their contribution to CP. In total, 24.7% of in iduals carried a P/LP variant(s) causing or increasing risk of CP, with 4.7% resolved by copy number variant analysis and 20% carrying single nucleotide or indel variants. A further 34.7% carried one or more rare, high impact variants of uncertain significance (VUS) in variation intolerant genes. Variants were identified in a heterogeneous group of genes, including genes associated with hereditary spastic paraplegia, clotting and thrombophilic disorders, small vessel disease, and other neurodevelopmental disorders. Approximately 1/2 of in iduals were classified as likely to benefit from changed clinical management as a result of genetic findings. In addition, no significant association between genetic findings and clinical factors was detectable in this cohort, suggesting that systematic sequencing of CP will be required to avoid missed diagnoses.
Publisher: Elsevier BV
Date: 08-2015
Publisher: Springer Science and Business Media LLC
Date: 11-01-2021
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1086/520677
Publisher: Springer Science and Business Media LLC
Date: 19-08-2007
DOI: 10.1038/NG2100
Publisher: Elsevier BV
Date: 08-2016
Publisher: Hindawi Limited
Date: 03-05-2021
DOI: 10.1002/HUMU.24207
Abstract: The pioneering discovery research of X-linked intellectual disability (XLID) genes has benefitted thousands of in iduals worldwide however, approximately 30% of XLID families still remain unresolved. We postulated that noncoding variants that affect gene regulation or splicing may account for the lack of a genetic diagnosis in some cases. Detecting pathogenic, gene-regulatory variants with the same sensitivity and specificity as structural and coding variants is a major challenge for Mendelian disorders. Here, we describe three pedigrees with suggestive XLID where distinctive phenotypes associated with known genes guided the identification of three different noncoding variants. We used comprehensive structural, single-nucleotide, and repeat expansion analyses of genome sequencing. RNA-Seq from patient-derived cell lines, reverse-transcription polymerase chain reactions, Western blots, and reporter gene assays were used to confirm the functional effect of three fundamentally different classes of pathogenic noncoding variants: a retrotransposon insertion, a novel intronic splice donor, and a canonical splice variant of an untranslated exon. In one family, we excluded a rare coding variant in ARX, a known XLID gene, in favor of a regulatory noncoding variant in OFD1 that correlated with the clinical phenotype. Our results underscore the value of genomic research on unresolved XLID families to aid novel, pathogenic noncoding variant discovery.
Publisher: Wiley
Date: 11-07-2013
DOI: 10.1096/FJ.12-224048
Abstract: Obesity is highly prevalent, and its incidence is increasing. The previous study showing a major effect of paternal obesity on metabolic health of offspring is confounded by comorbidity with diabetes. Therefore, we investigated the effect of diet-induced paternal obesity, in the absence of diabetes, on the metabolic health of two resultant generations and the molecular profiles of the testes and sperm. Founder (F0) male C57BL6 mice were fed either a high-fat diet (HFD) or a control diet (CD) n = 10/diet for a period of 10 wk. Testis expression of mRNA/microRNAs was analyzed by microarray and qPCR and sperm microRNA abundance by qPCR. Two subsequent generations were generated by mating F0 and then F1 mice to CD mice, and their metabolic health was investigated. All mice, other than F0 males, were maintained on a CD. HFD feeding induced paternal obesity with a 21% increase in adiposity, but not overt diabetes, and initiated intergenerational transmission of obesity and insulin resistance in two generations of offspring. This distinct phenotypic constellation is either partially or fully transmitted to both female and male F1 offspring and further transmitted through both parental lineages to the F2 generation, with a heightened effect on female F1 offspring (+67% in adiposity) and their F2 sons (+24% in adiposity). Founder male obesity altered the testes expression of 414 mRNAs by microarray and 11 microRNAs by qPCR, concomitant with alterations in sperm microRNA content and a 25% reduction in global methylation of germ cell DNA. Diet-induced paternal obesity modulates sperm microRNA content and germ cell methylation status, which are potential signals that program offspring health and initiate the transmission of obesity and impaired metabolic health to future generations. This study implicates paternal obesity in the transgenerational lification of obesity and type 2 diabetes in humans.
Publisher: Oxford University Press (OUP)
Date: 17-10-2018
DOI: 10.1093/HMG/DDY371
Publisher: Springer Science and Business Media LLC
Date: 08-2018
Publisher: Springer Science and Business Media LLC
Date: 14-06-2017
DOI: 10.1038/EJHG.2017.97
Publisher: Springer Science and Business Media LLC
Date: 02-2015
DOI: 10.1038/MP.2014.189
Abstract: Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.
Publisher: Elsevier BV
Date: 05-2011
Publisher: Oxford University Press (OUP)
Date: 11-12-2014
DOI: 10.1093/HMG/DDU614
Abstract: We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an ∼12-Mbp interval identical by descent (IBD) between the affected in iduals on chromosome 3q13.13-21.1 with an LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippoc al neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.EJMG.2017.06.002
Abstract: Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 (COL18A1): c.3690G > A: p.(Trp1230*) and NM_030582.3 (COL18A1): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected in iduals in the family. Identification of COL18A1 mutations in in iduals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2020
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1038/S41467-019-12763-9
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same in idual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
Publisher: Springer Science and Business Media LLC
Date: 23-04-2018
DOI: 10.1038/S41398-018-0136-4
Abstract: Cerebral palsy (CP) is the most common motor disability of childhood. It is characterised by permanent, non-progressive but not unchanging problems with movement, posture and motor function, with a highly heterogeneous clinical spectrum and frequent neurodevelopmental comorbidities. The aetiology of CP is poorly understood, despite recent reports of a genetic contribution in some cases. Here we demonstrate transcriptional dysregulation of trophic signalling pathways in patient-derived cell lines from an unselected cohort of 182 CP-affected in iduals using both differential expression analysis and weighted gene co-expression network analysis (WGCNA). We also show that genes differentially expressed in CP, as well as network modules significantly correlated with CP status, are enriched for genes associated with ASD. Combining transcriptome and whole exome sequencing (WES) data for this CP cohort likely resolves an additional 5% of cases separated to the 14% we have previously reported as resolved by WES. Collectively, these results support a convergent molecular abnormality in CP and ASD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-01-2022
DOI: 10.1212/NXG.0000000000000652
Abstract: The 2-hit model of genetic disease is well established in cancer, yet has only recently been reported to cause brain malformations associated with epilepsy. Pathogenic germline and somatic variants in genes in the mechanistic target of rapamycin (mTOR) pathway have been implicated in several malformations of cortical development. We investigated the 2-hit model by performing genetic analysis and searching for germline and somatic variants in genes in the mTOR and related pathways. We searched for germline and somatic pathogenic variants in 2 brothers with drug-resistant focal epilepsy and surgically resected focal cortical dysplasia (FCD) type IIA. Exome sequencing was performed on blood- and brain-derived DNA to identify pathogenic variants, which were validated by droplet digital PCR. In vitro functional assays of a somatic variant were performed. Exome analysis revealed a novel, maternally inherited, germline pathogenic truncation variant (c.48delG p.Ser17Alafs*70) in NPRL3 in both brothers. NPRL3 is a known FCD gene that encodes a negative regulator of the mTOR pathway. Somatic variant calling in brain-derived DNA from both brothers revealed a low allele fraction somatic variant (c.338C T p.Ala113Val) in the WNT2 gene in 1 brother, confirmed by droplet digital PCR. In vitro functional studies suggested a loss of WNT2 function as a consequence of this variant. A second somatic variant has not yet been found in the other brother. We identify a pathogenic germline mTOR pathway variant ( NPRL3 ) and a somatic variant ( WNT2 ) in the intersecting WNT signaling pathway, potentially implicating the WNT2 gene in FCD and supporting a dual-pathway 2-hit model. If confirmed in other cases, this would extend the 2-hit model to pathogenic variants in different genes in critical, intersecting pathways in a malformation of cortical development. Detection of low allele fraction somatic second hits is challenging but promises to unravel the molecular architecture of FCDs.
Publisher: Elsevier BV
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 22-04-2010
DOI: 10.1038/EJHG.2010.24
Publisher: Oxford University Press (OUP)
Date: 17-03-2017
DOI: 10.1093/HMG/DDX094
Publisher: Wiley
Date: 28-12-2015
DOI: 10.1002/AJMG.A.37527
Abstract: Mutations in COL4A1 are well described and result in brain abnormalities manifesting with severe neurological deficits including cerebral palsy, intellectual disability, and focal epilepsy. Families with mutations in COL4A2 are now emerging with a similar phenotype. We describe a family with an autosomal dominant disorder comprising porencephaly, focal epilepsy, and lens opacities, which was negative for mutations in COL4A1. Using whole exome sequencing of three affected in iduals from three generations, we identified a rare variant in COL4A2. This COL4A2 (c.2399G>A, p.G800E, CCDS41907.1) variant was predicted to be damaging by multiple bioinformatics tools and affects an invariable glycine residue that is essential for the formation of collagen IV heterotrimers. The cataracts identified in this family expand the phenotypic spectrum associated with mutations in COL4A2 and highlight the increasing overlap with phenotypes associated with COL4A1 mutations.
Publisher: Elsevier
Date: 2018
Publisher: Elsevier BV
Date: 08-2012
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.NBD.2018.05.004
Abstract: PCDH19-Girls Clustering Epilepsy (PCDH19-GCE) is a childhood epileptic encephalopathy characterised by a spectrum of neurodevelopmental problems. PCDH19-GCE is caused by heterozygous loss-of-function mutations in the X-chromosome gene, Protocadherin 19 (PCDH19) encoding a cell-cell adhesion molecule. Intriguingly, hemizygous males are generally unaffected. As PCDH19 is subjected to random X-inactivation, heterozygous females are comprised of a mosaic of cells expressing either the normal or mutant allele, which is thought to drive pathology. Despite being the second most prevalent monogeneic cause of epilepsy, little is known about the role of PCDH19 in brain development. In this study we show that PCDH19 is highly expressed in human neural stem and progenitor cells (NSPCs) and investigate its function in vitro in these cells of both mouse and human origin. Transcriptomic analysis of mouse NSPCs lacking Pcdh19 revealed changes to genes involved in regulation of neuronal differentiation, and we subsequently show that loss of Pcdh19 causes increased NSPC neurogenesis. We reprogramed human fibroblast cells harbouring a pathogenic PCDH19 mutation into human induced pluripotent stem cells (hiPSC) and employed neural differentiation of these to extend our studies into human NSPCs. As in mouse, loss of PCDH19 function caused increased neurogenesis, and furthermore, we show this is associated with a loss of human NSPC polarity. Overall our data suggests a conserved role for PCDH19 in regulating mammalian cortical neurogenesis and has implications for the pathogenesis of PCDH19-GCE. We propose that the difference in timing or "heterochrony" of neuronal cell production originating from PCDH19 wildtype and mutant NSPCs within the same in idual may lead to downstream asynchronies and abnormalities in neuronal network formation, which in-part predispose the in idual to network dysfunction and epileptic activity.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.GIM.2021.09.001
Abstract: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). A total of 74 families with erse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with s les from ≥2 affected in iduals or heterozygotes and 10 cases with ≥2 biospecimens. PCR licons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long licons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.
Publisher: Wiley
Date: 17-04-2023
DOI: 10.1111/EPI.17610
Abstract: Familial adult myoclonus epilepsy (FAME) is a genetic epilepsy syndrome that for many years has resisted understanding of its underlying molecular cause. This review covers the history of FAME genetic studies worldwide, starting with linkage and culminating in the discovery of noncoding TTTTA and inserted TTTCA pentanucleotide repeat expansions within six different genes to date ( SAMD12 , STARD7 , MARCHF6 , YEATS2 , TNRC6A , and RAPGEF2 ). FAME occurs worldwide however, repeat expansions in particular genes have regional geographical distributions. FAME repeat expansions are dynamic in nature, changing in length and structure within germline and somatic tissues. This variation poses challenges for molecular diagnosis such that molecular methods used to identify FAME repeat expansions typically require a trade‐off between cost and efficiency. A rigorous evaluation of the sensitivity and specificity of each molecular approach remains to be performed. The origin of FAME repeat expansions and the genetic and environmental factors that modulate repeat variability are not well defined. Longer repeats and particular arrangements of the TTTTA and TTTCA motifs within an expansion are correlated with earlier onset and increased severity of disease. Other factors such as maternal or paternal inheritance, parental age, and repeat length alone have been suggested to influence repeat variation however, further research is required to confirm this. The history of FAME genetics to the present is a chronicle of perseverance and predominantly collaborative efforts that yielded a successful outcome. The discovery of FAME repeats will spark progress toward a deeper understanding of the molecular pathogenesis of FAME, discovery of new loci, and development of cell and animal models.
Publisher: Wiley
Date: 23-11-2005
DOI: 10.1002/ANA.20305
Abstract: Nemaline myopathy is a human neuromuscular disorder associated with muscle weakness, Z-line accumulations (rods), and myofibrillar disorganization. Disease-causing mutations have been identified in genes encoding muscle thin filament proteins: actin, nebulin, slow troponin T, betaTropomyosin, and alphaTropomyosin(slow). Skeletal muscle expresses three tropomyosin (Tm) isoforms from separate genes: alphaTm(fast)(alphaTm, TPM1), betaTm (TPM2), and alphaTm(slow) (gammaTm, TPM3). In this article, we show that the level of betaTm, but not alphaTm(fast) protein, is reduced in human patients with mutations in alphaTm(slow) and in a transgenic mouse model of alphaTm(slow)(Met9Arg) nemaline myopathy. A postnatal time course of Tm expression in muscles of the mice indicated that the onset of alphaTm(slow)(Met9Arg) expression coincides with the decline of betaTm. Reduction of betaTm levels is independent of the degree of pathology (rods) within a muscle and is detected before the onset of muscle weakness. Thus, reduction in the level of betaTm represents an early clinical diagnostic marker for alphaTm(slow)-based mutations. Examinations of tropomyosin dimer formation using either recombinant proteins or sarcomeric extracts show that the mutation reduces the formation of the preferred alpha/beta heterodimer. We suggest this perturbation of tropomyosin isoform levels and dimer preference alters sarcomeric thin filament dynamics and contributes to muscle weakness in nemaline myopathy.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2015
DOI: 10.1038/MP.2014.193
Publisher: Hindawi Limited
Date: 15-06-2021
DOI: 10.1002/HUMU.24237
Abstract: PCDH19 is a nonclustered protocadherin molecule involved in axon bundling, synapse function, and transcriptional coregulation. Pathogenic variants in PCDH19 cause infantile-onset epilepsy known as PCDH19-clustering epilepsy or PCDH19-CE. Recent advances in DNA-sequencing technologies have led to a significant increase in the number of reported PCDH19-CE variants, many of uncertain significance. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. The application of the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines was only 50% accurate. Using a training set of 322 known benign or pathogenic missense variants, we identified MutPred2, MutationAssessor, and GPP as the best performing in silico tools. We generated a protein structural model of the extracellular domain and assessed 24 missense variants. We also assessed 24 variants using an in vitro reporter assay. A combination of these tools was 93% accurate in assessing known pathogenic and benign PCDH19 variants. We increased the accuracy of the ACMG-AMP classification of 45 PCDH19 variants from 50% to 94%, using these tools. In summary, we have developed a robust toolbox for the assessment of PCDH19 variant pathogenicity to improve the accuracy of PCDH19-CE variant classification.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2021
DOI: 10.1038/S41431-021-00889-8
Abstract: Inherited paediatric cataract is a rare Mendelian disease that results in visual impairment or blindness due to a clouding of the eye’s crystalline lens. Here we report an Australian family with isolated paediatric cataract, which we had previously mapped to Xq24. Linkage at Xq24–25 (LOD = 2.53) was confirmed, and the region refined with a denser marker map. In addition, two autosomal regions with suggestive evidence of linkage were observed. A segregating 127 kb deletion (chrX:g.118373226_118500408del) in the Xq24–25 linkage region was identified from whole-genome sequencing data. This deletion completely removed a commonly deleted long non-coding RNA gene LOC101928336 and truncated the protein coding progesterone receptor membrane component 1 ( PGRMC1 ) gene following exon 1. A literature search revealed a report of two unrelated males with non-syndromic intellectual disability, as well as congenital cataract, who had contiguous gene deletions that accounted for their intellectual disability but also disrupted the PGRMC1 gene. A morpholino-induced pgrmc1 knockdown in a zebrafish model produced significant cataract formation, supporting a role for PGRMC1 in lens development and cataract formation. We hypothesise that the loss of PGRMC1 causes cataract through disrupted PGRMC1-CYP51A1 protein–protein interactions and altered cholesterol biosynthesis. The cause of paediatric cataract in this family is the truncating deletion of PGRMC1 , which we report as a novel cataract gene.
Publisher: Elsevier BV
Date: 10-2021
Publisher: Oxford University Press (OUP)
Date: 26-03-2021
DOI: 10.1093/HMG/DDAB081
Abstract: The PHF6 mutation c.1024C & T p.R342X, is a recurrent cause of Börjeson–Forssman–Lehmann Syndrome (BFLS), a neurodevelopmental disorder characterized by moderate–severe intellectual disability, truncal obesity, gynecomastia, hypogonadism, long tapering fingers and large ears (MIM#301900). Here, we generated transgenic mice with the identical substitution (R342X mice) using CRISPR technology. We show that the p.R342X mutation causes a reduction in PHF6 protein levels, in both human and mice, from nonsense-mediated decay and nonsense-associated alternative splicing, respectively. Magnetic resonance imaging studies indicated that R342X mice had a reduced brain volume on a mixed genetic background but developed hydrocephaly and a high incidence of postnatal death on a C57BL/6 background. Cortical development proceeded normally, while hippoc us and hypothalamus relative brain volumes were altered. A hypoplastic anterior pituitary was also observed that likely contributes to the small size of the R342X mice. Behavior testing demonstrated deficits in associative learning, spatial memory and an anxiolytic phenotype. Taken together, the R342X mice represent a good preclinical model of BFLS that will allow further dissection of PHF6 function and disease pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2018
DOI: 10.1038/S41525-018-0073-4
Abstract: Cerebral palsy (CP) is the most frequent movement disorder of childhood affecting 1 in 500 live births in developed countries. We previously identified likely pathogenic de novo or inherited single nucleotide variants (SNV) in 14% (14/98) of trios by exome sequencing and a further 5% (9/182) from evidence of outlier gene expression using RNA sequencing. Here, we detected copy number variants (CNV) from exomes of 186 unrelated in iduals with CP (including our original 98 trios) using the CoNIFER algorithm. CNV were validated with Illumina 850 K SNP arrays and compared with RNA-Seq outlier gene expression analysis from lymphoblastoid cell lines (LCL). Gene expression was highly correlated with gene dosage effect. We resolved an additional 3.7% (7/186) of this cohort with pathogenic or likely pathogenic CNV while a further 7.7% (14/186) had CNV of uncertain significance. We identified recurrent genomic rearrangements previously associated with CP due to 2p25.3 deletion, 22q11.2 deletions and duplications and Xp monosomy. We also discovered a deletion of a single gene, PDCD6IP , and performed additional zebrafish model studies to support its single allele loss in CP aetiology. Combined SNV and CNV analysis revealed pathogenic and likely pathogenic variants in 22.7% of unselected in iduals with CP.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Springer Science and Business Media LLC
Date: 22-02-2012
DOI: 10.1038/EJHG.2012.9
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.GIM.2022.08.006
Abstract: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. Genetic information from 404 in iduals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished in iduals were collected and combined with 68 previously published in iduals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2022
DOI: 10.1038/S41525-021-00277-7
Abstract: TIMMDC1 encodes the T ranslocase of I nner M itochondrial M embrane D omain- C ontaining protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected children, now deceased, who presented with failure to thrive in the early postnatal period, poor feeding, hypotonia, peripheral neuropathy and drug-resistant epilepsy. Genome sequencing data revealed a known, deep intronic pathogenic variant TIMMDC1 c.597-1340A G, also present in gnomAD (~1/5000 frequency), that enhances aberrant splicing. Using RNA and protein analysis we show almost complete loss of TIMMDC1 protein and compromised mitochondrial complex I function. We have designed and applied two different splice-switching antisense oligonucleotides (SSO) to restore normal TIMMDC1 mRNA processing and protein levels in patients’ cells. Quantitative proteomics and real-time metabolic analysis of mitochondrial function on patient fibroblasts treated with SSOs showed restoration of complex I subunit abundance and function. SSO-mediated therapy of this inevitably fatal TIMMDC1 neurologic disorder is an attractive possibility.
Publisher: Oxford University Press (OUP)
Date: 16-07-2020
DOI: 10.1093/HMG/DDAA151
Abstract: Loss-of-function mutations of the X-chromosome gene UPF3B cause male neurodevelopmental disorders (NDDs) via largely unknown mechanisms. We investigated initially by interrogating a novel synonymous UPF3B variant in a male with absent speech. In silico and functional studies using cell lines derived from this in idual show altered UPF3B RNA splicing. The resulting mRNA species encodes a frame-shifted protein with a premature termination codon (PTC) predicted to elicit degradation via nonsense-mediated mRNA decay (NMD). UPF3B mRNA was reduced in the cell line, and no UPF3B protein was produced, confirming a loss-of-function allele. UPF3B is itself involved in the NMD mechanism which degrades both PTC-bearing mutant transcripts and also many physiological transcripts. RNAseq analysis showed that ~1.6% of mRNAs exhibited altered expression. These mRNA changes overlapped and correlated with those we identified in additional cell lines obtained from in iduals harbouring other UPF3B mutations, permitting us to interrogate pathogenic mechanisms of UPF3B-associated NDDs. We identified 102 genes consistently deregulated across all UPF3B mutant cell lines. Of the 51 upregulated genes, 75% contained an NMD-targeting feature, thus identifying high-confidence direct NMD targets. Intriguingly, 22 of the dysregulated genes encoded known NDD genes, suggesting UPF3B-dependent NMD regulates gene networks critical for cognition and behaviour. Indeed, we show that 78.5% of all NDD genes encode a transcript predicted to be targeted by NMD. These data describe the first synonymous UPF3B mutation in a patient with prominent speech and language disabilities and identify plausible mechanisms of pathology downstream of UPF3B mutations involving the deregulation of NDD-gene networks.
Publisher: Elsevier BV
Date: 05-2018
Publisher: Elsevier BV
Date: 10-2012
Publisher: Wiley
Date: 15-06-2020
DOI: 10.1111/DMCN.14585
Publisher: Elsevier BV
Date: 04-2015
Publisher: Springer Science and Business Media LLC
Date: 19-04-2009
DOI: 10.1038/NG.367
Publisher: Elsevier BV
Date: 03-2019
Publisher: Springer Science and Business Media LLC
Date: 04-11-2019
DOI: 10.1038/S41525-019-0101-Z
Abstract: A growing body of evidence points to a considerable and heterogeneous genetic aetiology of cerebral palsy (CP). To identify recurrently variant CP genes, we designed a custom gene panel of 112 candidate genes. We tested 366 clinically unselected singleton cases with CP, including 271 cases not previously examined using next-generation sequencing technologies. Overall, 5.2% of the naïve cases (14/271) harboured a genetic variant of clinical significance in a known disease gene, with a further 4.8% of in iduals (13/271) having a variant in a candidate gene classified as intolerant to variation. In the aggregate cohort of in iduals from this study and our previous genomic investigations, six recurrently hit genes contributed at least 4% of disease burden to CP: COL4A1 , TUBA1A, AGAP1 , L1CAM , MAOB and KIF1A . Significance of Rare VAriants (SORVA) burden analysis identified four genes with a genome-wide significant burden of variants, AGAP1 , ERLIN1 , ZDHHC9 and PROC , of which we functionally assessed AGAP1 using a zebrafish model. Our investigations reinforce that CP is a heterogeneous neurodevelopmental disorder with known as well as novel genetic determinants.
Publisher: Springer Science and Business Media LLC
Date: 11-2017
DOI: 10.1038/NATURE24484
Publisher: Public Library of Science (PLoS)
Date: 19-03-2015
Publisher: Springer Science and Business Media LLC
Date: 31-05-2019
DOI: 10.1038/S41525-019-0086-7
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Wiley
Date: 05-07-2019
DOI: 10.1111/CEO.13569
Abstract: Fuchs endothelial corneal dystrophy (FECD) is a progressive and potentially a sight threatening disease, and a common indication for corneal grafting in the elderly. Aberrant thickening of Descemet's membrane, formation of microscopic excrescences (guttae) and gradual loss of corneal endothelial cells are the hallmarks of the disease. The aim of this study was to identify differentially abundant proteins between FECD-affected and unaffected Descemet's membrane. Label-free quantitative proteomics using nanoscale ultra-performance liquid chromatography-mass spectrometry (nUPLC-MS Quantitative proteomics revealed significantly lower abundance of apolipoprotein E (APOE) and immunoglobulin heavy constant gamma 1 protein (IGHG1) in affected Descemet's membrane. The difference in the distribution of APOE between affected and unaffected Descemet's membrane and of IGHG1 detected by immunohistochemistry support their down-regulation in the disease. Comparative gene expression analysis showed significantly lower APOE mRNA levels in FECD-affected than unaffected corneal endothelium. IGHG1 gene is expressed at extremely low levels in the corneal endothelium, precluding relative expression analysis. This is the first study to report comparative proteomics of Descemet's membrane tissue, and implicates dysregulation of APOE and IGHG1 proteins in the pathogenesis of Fuchs endothelial corneal dystrophy.
Publisher: Oxford University Press (OUP)
Date: 29-06-2015
DOI: 10.1093/HMG/DDV245
Abstract: Protocadherin 19 (PCDH19) female limited epilepsy (PCDH19-FE also known as epilepsy and mental retardation limited to females, EFMR MIM300088) is an infantile onset epilepsy syndrome with or without intellectual disability (ID) and autism. We investigated transcriptomes of PCDH19-FE female and control primary skin fibroblasts, which are endowed to metabolize neurosteroid hormones. We identified a set of 94 significantly dysregulated genes in PCDH19-FE females. Intriguingly, 43 of the 94 genes (45.7%) showed gender-biased expression enrichment of such genes was highly significant (P = 2.51E-47, two-tailed Fisher exact test). We further investigated the AKR1C1-3 genes, which encode crucial steroid hormone-metabolizing enzymes whose key products include allopregnanolone and estradiol. Both mRNA and protein levels of AKR1C3 were significantly decreased in PCDH19-FE patients. In agreement with this, the blood levels of allopregnanolone were also (P < 0.01) reduced. In conclusion, we show that the deficiency of neurosteroid allopregnanolone, one of the most potent GABA receptor modulators, may contribute to PCDH19-FE. Overall our findings provide evidence for a role of neurosteroids in epilepsy, ID and autism and create realistic opportunities for targeted therapeutic interventions.
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.EPLEPSYRES.2013.02.005
Abstract: We describe the clinical and radiological features of a family with a homozygous mutation in TBC1D24. The phenotype comprised onset of focal seizures at 2 months with prominent eye-blinking, facial and limb jerking with an oral sensory aura. These were controllable with medication but persisted into adult life. Associated features were mild to moderate intellectual disability and cerebellar features. MRI showed subtle cortical thickening with cerebellar atrophy and high signal confined to the ansiform lobule. The disorder is allelic with familial infantile myoclonic epilepsy, where intellect and neurologic examination are normal, highlighting the phenotypic variation with mutations of TBC1D24.
Publisher: Informa UK Limited
Date: 10-2010
DOI: 10.1586/ERM.10.83
Publisher: Elsevier BV
Date: 2020
Publisher: The Endocrine Society
Date: 05-2015
DOI: 10.1210/JC.2014-4383
Abstract: 46,XX male sex reversal occurs in approximately 1: 20 000 live births and is most commonly caused by interchromosomal translocations of the Y-linked sex-determining gene, SRY. Rearrangements of the closely related SOX3 gene on the X chromosome are also associated with 46,XX male sex reversal. It has been hypothesized that sex reversal in the latter is caused by ectopic expression of SOX3 in the developing urogenital ridge where it triggers male development by acting as an analog of SRY. However, altered regulation of SOX3 in in iduals with XX male sex reversal has not been demonstrated. Here we report a boy with SRY-negative XX male sex reversal who was diagnosed at birth with a small phallus, mixed gonads, and borderline-normal T. Molecular characterization of the affected in idual was performed using array comparative genomic hybridization, fluorescent in situ hybridization of metaphase chromosomes, whole-genome sequencing, and RT-PCR expression analysis of lymphoblast cell lines. The affected male carries ∼774-kb insertion translocation from chromosome 1 into a human-specific palindromic sequence 82 kb distal to SOX3. Importantly, robust SOX3 expression was identified in cells derived from the affected in idual but not from control XX or XY cells, indicating that the translocation has a direct effect on SOX3 regulation. This is the first demonstration of altered SOX3 expression in an in idual with XX male sex reversal and suggests that SOX3 can substitute for SRY to initiate male development in humans.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2016
DOI: 10.1038/SREP27010
Abstract: There is an ever increasing body of evidence that demonstrates that paternal over-nutrition prior to conception programs impaired metabolic health in offspring. Here we examined whether paternal under-nutrition can also program impaired health in offspring and if any detrimental health outcomes in offspring could be prevented by micronutrient supplementation (vitamins and antioxidants). We discovered that restricting the food intake of male rodents reduced their body weight, fertility, increased sperm oxidative DNA lesions and reduced global sperm methylation. Under-nourished males then sired offspring with reduced postnatal weight and growth but somewhat paradoxically increased adiposity and dyslipidaemia, despite being fed standard chow. Paternal vitamin/antioxidant food fortification during under-nutrition not only normalised founder oxidative sperm DNA lesions but also prevented early growth restriction, fat accumulation and dyslipidaemia in offspring. This demonstrates that paternal under-nutrition reduces postnatal growth but increases the risk of obesity and metabolic disease in the next generation and that micronutrient supplementation during this period of under-nutrition is capable of restoring offspring metabolic health.
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.TIG.2009.05.002
Abstract: X-linked mental retardation (XLMR) or intellectual disability (ID) is a common, clinically complex and genetically heterogeneous disease arising from many mutations along the X chromosome. It affects between 1/600-1/1000 males and a substantial number of females. Research during the past decade has identified >90 different XLMR genes, affecting a wide range of cellular processes. Many more genes remain uncharacterized, especially for the non-syndromic XLMR forms. Currently, approximately 11% of X-chromosome genes are implicated in XLMR however, apart from a few notable exceptions, most contribute in idually to <0.1% of the total landscape, which arguably remains only about half complete. There remain many hills to climb and valleys to cross before the ID landscape is fully triangulated.
Publisher: Oxford University Press (OUP)
Date: 28-02-2013
DOI: 10.1093/BRAIN/AWT021
Abstract: We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.MODGEP.2007.06.007
Abstract: The Plant homeodomain finger gene 6 (PHF6) was identified as the gene mutated in patients suffering from the Börjeson-Forssman-Lehmann Syndrome (BFLS), an X-linked mental retardation disorder. BFLS mental disability is evident from an early age, suggesting a developmental brain defect. The PHF6 protein contains four nuclear localisation signals and two imperfect plant homeodomain (PHD) fingers similar to the third, imperfect PHD fingers in members of the trithorax family of transcriptional regulators. The PHF6 gene is highly conserved in vertebrate species. Despite the devastating effects of mutation of the PHF6 gene, nothing is known about the cellular function of PHF6. In order to lay the base for functional studies, we identify here the cell types that express the murine Phf6 gene and protein during prenatal and postnatal development. The Phf6 gene and protein are expressed widely. However, expression levels vary from strong to barely detectable. Strongest Phf6 gene expression and nuclear localisation of Phf6 protein were observed in the developing central nervous system, the anterior pituitary gland, the primordia of facial structures and the limb buds. Expression levels of both mRNA and protein decline over the course of development. In the adult brain moderate Phf6 expression is maintained in projection neurons, such as mitral cells in the olfactory bulb, cerebrocortical pyramidal cells and cerebellar Purkinje cells. Phf6 gene expression and nuclear localisation of Phf6 protein correlate with clinical symptoms in BFLS patients, namely mental disability, pan-anterior pituitary hormonal deficiency and facial as well digit abnormalities.
Publisher: Elsevier BV
Date: 11-2018
No related grants have been discovered for Mark Corbett.