Genetic analysis of contiguous X-chromosome deletion syndrome encompassing the BTK and TIMM8A genes

Arai, Takashi; Zhao, Meina; Kanegane, Hirokazu; Zelm, Menno C. van; Futatani, Takeshi; Yamada, Masafumi; Ariga, Tadashi; Ochs, Hans D.; Miyawaki, Toshio; Oh‐ishi, Tsutomu

doi:10.1038/jhg.2011.61

Cited by 19 publications

(14 citation statements)

References 22 publications

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“…The four patients described with the microdeletion spanning BTK, TIMM8A, TAF7L and DRP2 presented the typical X-linked agammaglobulinaemia and Mohr-Tranebjaerg syndrome phenotypes, but also autism and language delay. [43][44][45] Interestingly, a recent WES study reported the same mutation (E432*) that we found in DRP2 in one autistic family, which was absent from a large cohort of controls. 18 This work represents one of the first comprehensive studies of multiplex families with ASD by exome sequencing.…”

Section: Discussionsupporting

confidence: 48%

Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations

et al. 2013

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Autism is a severe neurodevelopmental disorder, the aetiology of which remains mainly unknown. Family and twin studies provide strong evidence that genetic factors have a major role in the aetiology of this disease. Recently, whole exome sequencing (WES) efforts have focused mainly on rare de novo variants in singleton families. Although these studies have provided pioneering insights, de novo variants probably explain only a small proportion of the autism risk variance. In this study, we performed exome sequencing of 10 autism multiplex families with the aim of investigating the role of rare variants that are coinherited in the affected sibs. The pool of variants selected in our study is enriched with genes involved in neuronal functions or previously reported in psychiatric disorders, as shown by Gene Ontology analysis and by browsing the Neurocarta database. Our data suggest that rare truncating heterozygous variants have a predominant role in the aetiology of autism. Using a multiple linear regression model, we found that the burden of truncating mutations correlates with a lower non-verbal intelligence quotient (NVIQ). Also, the number of truncating mutations that were transmitted to the affected sibs was significantly higher (twofold) than those not transmitted. Protein-protein interaction analysis performed with our list of mutated genes revealed that the postsynaptic YWHAZ is the most interconnected node of the network. Among the genes found disrupted in our study, there is evidence suggesting that YWHAZ and also the X-linked DRP2 may be considered as novel autism candidate genes.

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Section: Discussionsupporting

confidence: 48%

Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations

et al. 2013

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“…This 879aa protein is encoded by a 45kb gene localized to Xq22 and was originally described as being expressed principally in the brain and spinal cord [21]. Deletions spanning DRP2 alongside other X-linked genes such as BTK have been reported with agammaglobulinaemia and Mohr–Tranebjaerg syndrome [22-24]. More recently, DRP2 truncating mutations have been proposed as a potential cause of autism spectrum disorder though the mechanism remains to be elucidated [25].…”

Section: Discussionmentioning

confidence: 99%

Absence of Dystrophin Related Protein-2 disrupts Cajal bands in a patient with Charcot–Marie–Tooth disease

Brennan

Bai

Pisciotta

et al. 2015

Neuromuscular Disorders

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Using exome sequencing in an individual with Charcot-Marie-Tooth disease (CMT) we have identified a mutation in the X-linked dystrophin-related protein 2 (DRP2) gene. A 60-year-old gentleman presented to our clinic and underwent clinical, electrophysiological and skin biopsy studies. The patient had clinical features of a length dependent sensorimotor neuropathy with an age of onset of 50 years. Neurophysiology revealed prolonged latencies with intermediate conduction velocities but no conduction block or temporal dispersion. A panel of 23 disease causing genes was sequenced and ultimately was uninformative. Whole exome sequencing revealed a stop mutation in DRP2, c.805C>T (Q269*). DRP2 interacts with periaxin and dystroglycan to form the periaxin-DRP2-dystroglycan complex which plays a role in the maintenance of the well-characterized Cajal bands of myelinating Schwann cells. Skin biopsies from our patient revealed a lack of DRP2 in myelinated dermal nerves by immunofluorescence. Furthermore electron microscopy failed to identify Cajal bands in the patient's dermal myelinated axons in keeping with ultrastructural pathology seen in the Drp2 knockout mouse. Both the electrophysiologic and dermal nerve twig pathology support the interpretation that this patient's DRP2 mutation causes characteristic morphological abnormalities recapitulating the Drp2 knockout model and potentially represents a novel genetic cause of CMT.

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“…The human genome project hg18 identified 584 human reference-specific Alu insertions [43]. Alu insertion can influence the genome stability, and it accounts for 0.1% of all human genetic disorders [9] such as hereditary desmoid disease [50], cystic fibrosis [51], Dent's disease [52, 53], X-linked agammaglobulinemia [54–57], hemophilia A and B [58–60], autoimmune lymphoproliferative syndrome [61], Apert syndrome [62], neurofibromatosis type 1 [63], benign isolated glycerol kinase deficiency [64], hyper IgM with immunodeficiency syndrome [65], Menkes disease [66], Alstrom syndrome [67], retinitis pigmentosa [68], acholinesterasemia [69], autosomal dominant optic atrophy [70], hemolytic anemia [24], autosomal branchio-oto-renal syndrome [71], acute intermittent porphyria [72], mucolipidosis II [73], and several type of cancer [23, 74–77] to cite a few. There are several mechanisms by which Alu can alter genomic structure.…”

Section: Alu-mediated Recombination and Insertional Mutagenesis Comentioning

confidence: 99%

AluMobile Elements: From Junk DNA to Genomic Gems

Dridi

2012

Scientifica

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Alus, the short interspersed repeated sequences (SINEs), are retrotransposons that litter the human genomes and have long been considered junk DNA. However, recent findings that these mobile elements are transcribed, both as distinct RNA polymerase III transcripts and as a part of RNA polymerase II transcripts, suggest biological functions and refute the notion that Alus are biologically unimportant. Indeed, Alu RNAs have been shown to control mRNA processing at several levels, to have complex regulatory functions such as transcriptional repression and modulating alternative splicing and to cause a host of human genetic diseases. Alu RNAs embedded in Pol II transcripts can promote evolution and proteome diversity, which further indicates that these mobile retroelements are in fact genomic gems rather than genomic junks.

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Genetic analysis of contiguous X-chromosome deletion syndrome encompassing the BTK and TIMM8A genes

Cited by 19 publications

References 22 publications

Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations

Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations

Absence of Dystrophin Related Protein-2 disrupts Cajal bands in a patient with Charcot–Marie–Tooth disease

AluMobile Elements: From Junk DNA to Genomic Gems

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