Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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A non-coding mutation implicates HCFC1 in non-syndromic intellectual disability

ABSTRACT: Human disease mutation discovery has so far been biased towards protein coding regions. Having excluded all annotated coding regions, we performed targeted massively parallel re-sequencing of the non-repetitive genomic linkage interval of the MRX3 family at Xq28. We identified a regulatory mutation in the YY1 transcription factor binding site, which leads to overexpression of the chromatin-associated transcriptional regulator, HCFC1. When tested on embryonic murine neural stem cells (NSCs) and embryonic hippocampal neurons, HCFC1 overexpression led to a significant increase of the production of astrocytes and considerable reduction in neurite growth. Two other non-synonymous, potentially deleterious changes have been identified by X-exome sequencing in individuals with intellectual disability, implicating HCFC1 in normal brain function. Total RNA was extracted from LCL derived from four unrelated male controls, five unrelated female controls and two affected male cousins from the MRX3 family.

ORGANISM(S): Homo sapiens

SUBMITTER: Mark Corbett

PROVIDER: E-GEOD-39326 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The Wiskott-Aldrich Syndrome Protein (WASP) family is known for its participation in cytoskeleton reorganization (Marchand et al., 2001 and Jia et al., 2010). In 2007, the human subtelomeric MGC52000 genes were renamed as Wiskott-Aldrich Syndrome Protein and SCAR Homolog (WASH). Human WASH proteins are part of the WASP protein family and colocalize with actin in cells and promote Arp2/3-dependent actin polymerization in vitro (Linardopoulou et al., 2007). WASH multiprotein complex consists of seven subunits: notable to mention Strumpelin and Was Protein Family Homolog (WASH)-interacting protein (SWIP), which is encoded by KIAA1033/WASHC4 gene, FAM21 and Arp2/3. The Arp2/3 dependent actin polymerization from G-actin to F-actin is an important step in regulation of the cytoskeleton, enabling multiple endosomal transport processes (Kelleher et al., 1995 and Derivery et al., 2010). Linardopoulou and colleagues have also shown in an animal model (Drosophila), that the single WASH ortholog is essential for viability (Linardopoulou et al., 2007), strengthening the concept, that WASHC4 plays a crucial role in muscle cell integrity and function. A link between autosomal recessive intellectual disability (ARID) and mutations in the KIAA1033/WASHC4 gene was first recognized in 2011 by Ropers and colleagues. Very recently, Assoum and colleagues reported three additional patients (from two unrelated families) with syndromic ID. Two of them being sisters (8 and 6 years), both presenting with learning disabilities, macrocephaly, dysmorphic features, skeletal anomalies and subependymal heterotopic nodules due to a compound heterozygous mutation of the KIAA1033/WASHC4 gene (p.[Gln442*] and p.[Asp1048Gly]). In this study, we precisely describe the clinical phenotype of the two siblings and provide additional information (histological and proteomic data) derived from the muscle biopsy of the elder sibling to confirm the pathogenicity of the reported variant and establish the function of WASHC4 as relevant for muscle homeostasis. Which, as far as the authors know, has not yet been described in literature.

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A non-coding mutation implicates HCFC1 in non-syndromic intellectual disability

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