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|Title:||A focal Eeilepsy and intellectual disability syndrome is due to a mutation in TBC1D24|
|Citation:||American Journal of Human Genetics, 2010; 87(3):371-375|
|Publisher:||Univ Chicago Press|
|Mark A. Corbett, Melanie Bahlo, Lachlan Jolly, Zaid Afawi, Alison E. Gardner, Karen L. Oliver, Stanley Tan, Amy Coffey, John C. Mulley, Leanne M. Dibbens, Walid Simri, Adel Shalata, Sara Kivity, Graeme D. Jackson, Samuel F. Berkovic, and Jozef Gecz|
|Abstract:||We characterized an autosomal-recessive syndrome of focal epilepsy, dysarthria, and mild to moderate intellectual disability in a consanguineous Arab-Israeli family associated with subtle cortical thickening. We used multipoint linkage analysis to map the causative mutation to a 3.2 Mb interval within 16p13.3 with a LOD score of 3.86. The linked interval contained 160 genes, many of which were considered to be plausible candidates to harbor the disease-causing mutation. To interrogate the interval in an efficient and unbiased manner, we used targeted sequence enrichment and massively parallel sequencing. By prioritizing unique variants that affected protein translation, a pathogenic mutation was identified in TBC1D24 (p.F251L), a gene of unknown function. It is a member of a large gene family encoding TBC domain proteins with predicted function as Rab GTPase activators. We show that TBC1D24 is expressed early in mouse brain and that TBC1D24 protein is a potent modulator of primary axonal arborization and specification in neuronal cells, consistent with the phenotypic abnormality described.|
|Keywords:||Neurons; Axons; Animals; Humans; Mice; Epilepsies, Partial; Syndrome; GTPase-Activating Proteins; Carrier Proteins; Membrane Proteins; Nerve Tissue Proteins; Chromosome Mapping; Pedigree; Cell Shape; Amino Acid Sequence; Mutation; Open Reading Frames; Molecular Sequence Data; Infant; Female; Male; Intellectual Disability|
|Rights:||© 2010 The American Society of Human Genetics|
|Appears in Collections:||Molecular and Biomedical Science publications|
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