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Am J Hum Genet. 2010 Sep 10;87(3):371-5. doi: 10.1016/j.ajhg.2010.08.001.

A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24.

Author information

1
Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia.

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.

PMID:
20797691
PMCID:
PMC2933342
DOI:
10.1016/j.ajhg.2010.08.001
[Indexed for MEDLINE]
Free PMC Article

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