TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease

Hum Mutat. 2014 Apr;35(4):447-51. doi: 10.1002/humu.22529.


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.

Keywords: TBC1D7; TSC; exome sequencing; intellectual disability; mTORC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Autophagy
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Celiac Disease / genetics*
  • Celiac Disease / pathology
  • Cell Cycle Proteins
  • Cell Line
  • Exome
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • High-Throughput Nucleotide Sequencing
  • Homozygote
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Intracellular Signaling Peptides and Proteins
  • Megalencephaly / genetics*
  • Megalencephaly / pathology
  • Mutation
  • Patellar Dislocation / genetics*
  • Patellar Dislocation / pathology
  • Pedigree
  • Phosphoproteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • TBC1D7 protein, human