Key result
A novel homozygous TBC1D7 truncating mutation in two sisters was associated with a broadened syndromic phenotype including macrocephaly, intellectual disability, and altered mTORC1 signaling.
Case Report (n=2)
Expands the phenotypic spectrum of TBC1D7 mutations to include osteoarticular defects and celiac disease, defining a TBC1D7 syndrome linked to altered mTORC1 signaling and autophagy.
TBC1D7 forms a complex with TSC1 and TSC2 that inhibits mTORC1 signaling and limits cell growth. Mutations in TBC1D7 were reported in a family with intellectual disability (ID) and macrocrania. Using exome sequencing, we identified two sisters homozygote for the novel c.17_20delAGAG, p.R7TfsX21 TBC1D7 truncating mutation. In addition to the already described macrocephaly and mild ID, they share osteoarticular defects, patella dislocation, behavioral abnormalities, psychosis, learning difficulties, celiac disease, prognathism, myopia, and astigmatism. Consistent with a loss-of-function of TBC1D7, the patient's cell lines show an increase in the phosphorylation of 4EBP1, a direct downstream target of mTORC1 and a delay in the initiation of the autophagy process. This second family allows enlarging the phenotypic spectrum associated with TBC1D7 mutations and defining a TBC1D7 syndrome. Our work reinforces the involvement of TBC1D7 in the regulation of mTORC1 pathways and suggests an altered control of autophagy as possible cause of this disease.
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Alfaiz et al. (2014) conducted a case report in TBC1D7 mutation syndrome (n=2). TBC1D7 truncating mutation (c.17_20delAGAG, p.R7TfsX21) was evaluated on Phenotypic features and cellular signaling changes. A novel homozygous TBC1D7 truncating mutation in two sisters was associated with a broadened syndromic phenotype including macrocephaly, intellectual disability, and altered mTORC1 signaling.
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