Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly

Mutations in TSC1 or TSC2 cause Tuberous Sclerosis Complex (TSC) a multisystemic disorder with many features including intellectual disability (ID). TSC1, TSC2 and TBC1D7 form a complex that inhibits mTORC1 signaling and limits cell growth. Using homozygosity mapping and exome sequencing to study a consanguineous family with ID and megalencephaly, we identified, in the affected individuals, a homozygous truncating mutation in TBC1D7. This mutation (p.Y180fsX1) abolishes TBC1D7 expression and is associated with increased mTORC1 signaling in cells of the affected individuals. Our study shows that disruption of TBC1D7 causes ID but without the other typical features found in TSC. (By Fadi F. Hamdan, PhD, http://jmg.bmj.com/content/early/2013/05/16/jmedgenet-2013-101680 )