A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24.
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.
Corbett
Mark A
MA
Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia.
Bahlo
Melanie
M
Jolly
Lachlan
L
Afawi
Zaid
Z
Gardner
Alison E
AE
Oliver
Karen L
KL
Tan
Stanley
S
Coffey
Amy
A
Mulley
John C
JC
Dibbens
Leanne M
LM
Simri
Walid
W
Shalata
Adel
A
Kivity
Sara
S
Jackson
Graeme D
GD
Berkovic
Samuel F
SF
Gecz
Jozef
J
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
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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