title: A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24.
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.
authors.affiliation: Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Corbett
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: Lachlan
authors.initials: L
authors.lastname: Jolly
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.forename: Alison E
authors.initials: AE
authors.lastname: Gardner
authors.forename: Karen L
authors.initials: KL
authors.lastname: Oliver
authors.forename: Stanley
authors.initials: S
authors.lastname: Tan
authors.forename: Amy
authors.initials: A
authors.lastname: Coffey
authors.forename: John C
authors.initials: JC
authors.lastname: Mulley
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.forename: Walid
authors.initials: W
authors.lastname: Simri
authors.forename: Adel
authors.initials: A
authors.lastname: Shalata
authors.forename: Sara
authors.initials: S
authors.lastname: Kivity
authors.forename: Graeme D
authors.initials: GD
authors.lastname: Jackson
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D048430:Cell Shape; D002874:Chromosome Mapping; D004828:Epilepsies, Partial / Q000150:complications* / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000150:complications* / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000473:pathology; D016366:Open Reading Frames / Q000235:genetics; D010375:Pedigree; D013577:Syndrome
chemical_list: D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C552551:TBC1D24 protein, human; C552552:Tbc1d24 protein, mouse
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