A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet

Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Nature Genetics (Impact Factor: 29.35). 05/2009; 41(5):535-43. DOI: 10.1038/ng.367
Source: PubMed


Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.

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Available from: Jozef Gecz
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    • "Several attempts have been made in the recent past to accelerate the discovery of novel neurological disease genes. One of the earliest attempts was the high-throughput Sanger sequencing of all coding exons on the X chromosome in a large cohort of >200 families with suspected X-linked intellectual disability (Tarpey et al., 2009). In addition to the laborious nature of this approach, the yield was somewhat modest (three novel genes) partly because enrichment for novel gene discovery was not feasible, and also partly due to a large proportion of X-linked disease genes having already been established (de Brouwer et al., 2007). "
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    ABSTRACT: Neurogenetic disorders represent the largest category of Mendelian diseases in humans. They encompass a wide array of clinical presentations that range from the common e.g., intellectual disability (>1%) to the very rare, e.g., neurodegeneration with brain iron accumulation (one to three per 106) (Kalman et al., 2012 and Maulik et al., 2011). The highly prevalent involvement of the nervous system in many Mendelian disorders coincides with the observation that >80% of all human genes are expressed at some stage of brain development (Hawrylycz et al., 2012) and suggests that the brain is one of the most vulnerable organs to genetic perturbation. In fact high-resolution microarray analysis of the human genome reveals that intellectual disability is the common phenotypic denominator of genomic disorders that involve losses or gains of genes (Coe et al., 2012).
    Full-text · Article · Dec 2014 · Cell Reports
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    • "Our previous studies showed that TBR1 interacts with CASK (calcium/calmodulin-dependent serine protein kinase; Hsueh et al., 2000; Hsueh, 2009). Mutations in the CASK gene result in X-linked mental retardation (Najm et al., 2008; Tarpey et al., 2009; Moog et al., 2011). The CASK-TBR1 protein complex regulates the expression of glutamate receptor, ionotropic, N-methyl-D-aspartate 2B (Grin2b, also known as Nmdar2b; Wang et al., 2004a,b), which is critical for learning and memory and involved in autism and schizophrenia (Kristiansen et al., 2010; O’Roak et al., 2012b). "
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    ABSTRACT: The activity-regulated gene expression of transcription factors is required for neural plasticity and function in response to neuronal stimulation. T-brain-1 (TBR1), a critical neuron-specific transcription factor for forebrain development, has been recognized as a high-confidence risk gene for autism spectrum disorders (ASDs). Here, we show that in addition to its role in brain development, Tbr1 responds to neuronal activation and further modulates the Grin2b expression in adult brains and mature neurons. The expression levels of Tbr1 were investigated using both immunostaining and quantitative RT-PCR analyses. We found that the mRNA and protein expression levels of Tbr1 are induced by excitatory synaptic transmission driven by bicuculline or glutamate treatment in cultured mature neurons. The upregulation of Tbr1 expression requires the activation of both AMPA and NMDA receptors. Furthermore, behavioral training triggers Tbr1 induction in the adult mouse brain. The elevation of Tbr1 expression is associated with Grin2b upregulation in both mature neurons and adult brains. Using Tbr1-deficient neurons, we further demonstrated that TBR1 is required for the induction of Grin2b upon neuronal activation. Taken together with the previous studies showing that TBR1 binds the Grin2b promoter and controls expression of luciferase reporter driven by Grin2b promoter, the evidence suggests that TBR1 directly controls Grin2b expression in mature neurons. We also found that the addition of the calcium-calmodulin kinase II (CaMKII) antagonist KN-93, but not the calcium-dependent phosphatase calcineurin antagonist cyclosporin A, to cultured mature neurons noticeably inhibited Tbr1 induction, indicating that neuronal activation upregulates Tbr1 expression in a CaMKII-dependent manner. In conclusion, our study suggests that Tbr1 plays an important role in adult mouse brains in response to neuronal activation to modulate the activity-regulated gene transcription required for neural p
    Full-text · Article · Sep 2014 · Frontiers in Cellular Neuroscience
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    • "Mutations in such proteins have been found to interfere with normal brain development manifested during the developmental period, thus causing severe mental retardation. They have been associated with non-syndromic X-linked mental retardation [ZNF81: OMIM 314998 [18]; ZNF674: OMIM 300573 [19], ZNF711: OMIM 300803 [20], autosomal recessive non-syndromic intellectual disability [ZC3H14, OMIM 613279] [21] and impairment in adaptive behavior that manifest during development. "
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    ABSTRACT: Background A consanguineous Arab family is affected by an apparently novel autosomal recessive disorder characterized by cognitive impairment, failure-to-thrive, hypotonia and dysmorphic features including bilateral ptosis and epicanthic folds, synophrys, midface hypoplasia, downturned mouth corners, thin upper vermillion border and prominent ears, bilateral 5th finger camptodactyly, bilateral short 4th metatarsal bones, and limited knee mobility bilaterally. Methods The family was studied by homozygosity mapping, candidate gene mutation screening and whole Exome Next Generation Sequencing of a single affected member to identify the offending gene and mutation. The mutated gene product was studied by structural bioinformatics methods. Results A damaging c.C5054G mutation affecting an evolutionary highly conserved amino acid p.S1685W was identified in the ZNF407 gene at 18q23. The Serine to Tryptophane mutation affects two of the three ZNF407 isoforms and is located in the last third of the protein, in a linker peptide adjoining two zinc-finger domains. Structural analyses of this mutation shows disruption of an H-bond that locks the relative spatial position of the two fingers, leading to a higher flexibility of the linker and thus to a decreased probability of binding to the target DNA sequence essentially eliminating the functionality of downstream domains and interfering with the expression of various genes under ZNF407 control during fetal brain development. Conclusions ZNF407 is a transcription factor with an essential role in brain development. When specific and limited in number homozygosity intervals exist that harbor the offending gene in consanguineous families, Whole Exome Sequencing of a single affected individual is an efficient approach to gene mapping and mutation identification.
    Full-text · Article · Jun 2014 · Orphanet Journal of Rare Diseases
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