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Hunters Hill, Australia

Rujirabanjerd S.,Prince of Songkla University | Nelson J.,Genetic Service of Western Australia | Tarpey P.S.,Wellcome Trust Sanger Institute | Hackett A.,GOLD Service | And 10 more authors.
European Journal of Human Genetics

Mental retardation (MR) is characterized by cognitive impairment with an IQ 70. Many of the major causes are genetically determined and the 30% male excess suggests that mutations in genes carried on the X chromosome are disproportionably represented. One such gene, jumonji AT-rich interactive domain 1C (JARID1C) on Xp11.2, has been identified in families with X-linked MR (XLMR), with 18 different mutations reported to date. As part of a systematic resequencing of 720 genes in 208 XLMR families of the International Genetic of Learning Disability (IGOLD) consortium, two novel nucleotide changes in the JARID1C coding region were identified, with the nucleotide changes segregating with the disease phenotype in the two families. The first mutation is a single-nucleotide insertion in exon 21 (c.3258-3259insC p.K1087fs 43) causing a frameshift and resulting in a premature termination codon (PTC). Such PTC-containing mRNAs are generally degraded by nonsense-mediated mRNA decay (NMD) surveillance, but our results show that this is not the case with this mutation. The other change is a single-nucleotide substitution in exon 12 (c.1160C>A) in a published family with nonsyndromic MR, MRX13. This change occurs in a highly conserved amino acid, with proline (P) being substituted by threonine (T) (p.P544T). Functional analysis shows that this amino-acid substitution compromises both tri-and didemethylase activity of the JARID1C protein. We conclude that the two novel changes impair JARID1C protein function and are disease-causing mutations in these families. © 2010 Macmillan Publishers Limited All rights reserved. Source

Jensen L.R.,Max Planck Institute for Molecular Genetics | Bartenschlager H.,University of Hohenheim | Rujirabanjerd S.,SA Pathology and Womens and Childrens Hospital | Tzschach A.,Max Planck Institute for Molecular Genetics | And 16 more authors.

Background. Mental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome alone. In addition the majority of patients are non-syndromic in that they do not present with clinically recognisable features. This makes it difficult to determine the molecular cause of this disorder on the basis of the phenotype alone. Mutations in KDM5C (previously named SMCX or JARID1C), a gene that encodes a transcriptional regulator with histone demethylase activity specific for dimethylated and trimethylated H3K4, are a comparatively frequent cause of non-syndromic X-linked mental retardation (NS-XLMR). Specific transcriptional targets of KDM5C, however, are still unknown and the effects of KDM5C deficiency on gene expression have not yet been investigated. Results. By whole-mount in situ hybridisation we showed that the mouse homologue of KDM5C is expressed in multiple tissues during mouse development. We present the results of gene expression profiling performed on lymphoblastoid cell lines as well as blood from patients with mutations in KDM5C. Using whole genome expression arrays and quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) experiments, we identified several genes, including CMKOR1, KDM5B and KIAA0469 that were consistently deregulated in both tissues. Conclusions. Our findings shed light on the pathological mechanisms underlying mental retardation and have implications for future diagnostics of this heterogeneous disorder. © 2010 Jensen et al; licensee BioMed Central Ltd. Source

Hynes K.,SA Pathology | Hynes K.,University of Adelaide | Tarpey P.,Wellcome Trust Sanger Institute | Dibbens L.M.,SA Pathology | And 18 more authors.
Journal of Medical Genetics

Background: Epilepsy and mental retardation limited to females (EFMR) is an intriguing X-linked disorder affecting heterozygous females and sparing hemizygous males. Mutations in the protocadherin 19 (PCDH19) gene have been identified in seven unrelated families with EFMR. Methods and results: Here, we assessed the frequency of PCDH19 mutations in individuals with clinical features which overlap those of EFMR. We analysed 185 females from three cohorts: 42 with Rett syndrome who were negative for MECP2 and CDKL5 mutations, 57 with autism spectrum disorders, and 86 with epilepsy with or without intellectual disability. No mutations were identified in the Rett syndrome and autism spectrum disorders cohorts suggesting that despite sharing similar clinical characteristics with EFMR, PCDH19 mutations are not generally associated with these disorders. Among the 86 females with epilepsy (of whom 51 had seizure onset before 3 years), with or without intellectual disability, we identified two (2.3%) missense changes. One (c.1671C→G, p.N557K), reported previously without clinical data, was found in two affected sisters, the first EFMR family without a multigenerational family history of affected females. The second, reported here, is a novel de novo missense change identified in a sporadic female. The change, p.S276P, is predicted to result in functional disturbance of PCDH19 as it affects a highly conserved residue adjacent to the adhesion interface of EC3 of PCDH19. Conclusions: This de novo PCDH19 mutation in a sporadic female highlights that mutational analysis should be considered in isolated instances of girls with infantile onset seizures and developmental delay, in addition to those with the characteristic family history of EFMR. Source

Jensen L.R.,Max Planck Institute for Molecular Genetics | Chen W.,Max Planck Institute for Molecular Genetics | Moser B.,Max Planck Institute for Molecular Genetics | Lipkowitz B.,Max Planck Institute for Molecular Genetics | And 19 more authors.
European Journal of Human Genetics

X-linked intellectual disability (XLID), also known as X-linked mental retardation, is a highly genetically heterogeneous condition for which mutations in 90 different genes have been identified. In this study, we used a custom-made sequencing array based on the Affymetrix 50k platform for mutation screening in 17 known XLID genes in patients from 135 families and found eight single-nucleotide changes that were absent in controls. For four mutations affecting ATRX (p.1761MT), PQBP1 (p.155RX) and SLC6A8 (p.390PL and p.477SL), we provide evidence for a functional involvement of these changes in the aetiology of intellectual disability. © 2011 Macmillan Publishers Limited All rights reserved. Source

Nguyen L.S.,University of Adelaide | Jolly L.,SA Pathology | Shoubridge C.,University of Adelaide | Chan W.K.,University of Texas M. D. Anderson Cancer Center | And 20 more authors.
Molecular Psychiatry

The nonsense-mediated mRNA decay (NMD) pathway was originally discovered by virtue of its ability to rapidly degrade aberrant mRNAs with premature termination codons. More recently, it was shown that NMD also directly regulates subsets of normal transcripts, suggesting that NMD has roles in normal biological processes. Indeed, several NMD factors have been shown to regulate neurological events (for example, neurogenesis and synaptic plasticity) in numerous vertebrate species. In man, mutations in the NMD factor gene UPF3B, which disrupts a branch of the NMD pathway, cause various forms of intellectual disability (ID). Using Epstein Barr virus-immortalized B cells, also known as lymphoblastoid cell lines (LCLs), from ID patients that have loss-of-function mutations in UPF3B, we investigated the genome-wide consequences of compromised NMD and the role of NMD in neuronal development and function. We found that 5% of the human transcriptome is impacted in UPF3B patients. The UPF3B paralog, UPF3A, is stabilized in all UPF3B patients, and partially compensates for the loss of UPF3B function. Interestingly, UPF3A protein, but not mRNA, was stabilised in a quantitative manner that inversely correlated with the severity of patients' phenotype. This suggested that the ability to stabilize the UPF3A protein is a crucial modifier of the neurological symptoms due to loss of UPF3B. We also identified ARHGAP24, which encodes a GTPase-activating protein, as a canonical target of NMD, and we provide evidence that deregulation of this gene inhibits axon and dendrite outgrowth and branching. Our results demonstrate that the UPF3B-dependent NMD pathway is a major regulator of the transcriptome and that its targets have important roles in neuronal cells. © 2012 Macmillan Publishers Limited All rights reserved. Source

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