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 with...

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Bibliographic Details
Published in:American journal of human genetics 2010-09, Vol.87 (3), p.371-375
Main Authors: Corbett, Mark A., Bahlo, Melanie, Jolly, Lachlan, Afawi, Zaid, Gardner, Alison E., Oliver, Karen L., Tan, Stanley, Coffey, Amy, Mulley, John C., Dibbens, Leanne M., Simri, Walid, Shalata, Adel, Kivity, Sara, Jackson, Graeme D., Berkovic, Samuel F., Gecz, Jozef
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Axons - metabolism
Biological and medical sciences
Carrier Proteins - chemistry
Carrier Proteins - genetics
Cell Shape
Chromosome Mapping
Developmental disabilities
Epilepsies, Partial - complications
Epilepsies, Partial - genetics
Epilepsy
Female
Fundamental and applied biological sciences. Psychology
General aspects. Genetic counseling
Genes
Genetics
Genetics of eukaryotes. Biological and molecular evolution
GTPase-Activating Proteins - chemistry
GTPase-Activating Proteins - genetics
Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy
Humans
Infant
Intellectual Disability - complications
Intellectual Disability - genetics
Male
Medical genetics
Medical sciences
Mice
Molecular and cellular biology
Molecular Sequence Data
Mutation
Mutation - genetics
Nervous system (semeiology, syndromes)
Neurology
Neurons - pathology
Open Reading Frames - genetics
Pedigree
Proteins
Syndrome
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Description
Summary: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.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2010.08.001