TBC1D7 Mutations are Associated with Intellectual Disability, Macrocrania, Patellar Dislocation, and Celiac Disease. Issue 4 (April 2014)

• Record Type: Journal Article
• Authors: Alfaiz, Ali Abdullah; Micale, Lucia; Mandriani, Barbara; Augello, Bartolomeo; Pellico, Maria Teresa; Chrast, Jacqueline; Xenarios, Ioannis; Zelante, Leopoldo; Merla, Giuseppe; Reymond, Alexandre
• Is Part Of: Human mutation. Volume 35:Issue 4(2014:Apr.)
• Page Start: 447
• Page End: 451
• Publication Date: 2014-04
• Subjects: Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.22529
• Languages: English
• ISSNs: 1059-7794

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>TBC1D7 forms a complex with TSC1 and TSC2 that inhibits mTORC1 signaling and limits cell growth. Mutations in <italic>TBC1D7</italic> 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 <italic>TBC1D7</italic> 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 <italic>TBC1D7</italic>, 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 <italic>TBC1D7</italic> mutations and defining a <italic>TBC1D7</italic> 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.</p> </abstract>