TBC1D7Mutations are Associated with Intellectual Disability, Macrocrania, Patellar Dislocation, and Celiac Disease

Human MutationVolume 35, Issue 4 p. 447-451 Brief Report TBC1D7 Mutations are Associated with Intellectual Disability, Macrocrania, Patellar Dislocation, and Celiac Disease Ali Abdullah Alfaiz, Ali Abdullah Alfaiz Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland These authors contributed equally to this work.Search for more papers by this authorLucia Micale, Lucia Micale Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy These authors contributed equally to this work.Search for more papers by this authorBarbara Mandriani, Barbara Mandriani Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, ItalySearch for more papers by this authorBartolomeo Augello, Bartolomeo Augello Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, ItalySearch for more papers by this authorMaria Teresa Pellico, Maria Teresa Pellico Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, ItalySearch for more papers by this authorJacqueline Chrast, Jacqueline Chrast Center for Integrative Genomics, University of Lausanne, Lausanne, SwitzerlandSearch for more papers by this authorIoannis Xenarios, Ioannis Xenarios Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland Swiss Institute of Bioinformatics (SIB), Lausanne, SwitzerlandSearch for more papers by this authorLeopoldo Zelante, Leopoldo Zelante Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, ItalySearch for more papers by this authorGiuseppe Merla, Corresponding Author Giuseppe Merla Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland PhD Program, Scienze della Riproduzione e dello Sviluppo, University of Trieste, Trieste, Italy These senior authors contributed equally to this work.Correspondence to: Alexandre Reymond, Center for Integrative Genomics, University of Lausanne, Genopode building, 1015 Lausanne, Switzerland. E-mail: alexandre.reymond@unil.ch; Giuseppe Merla, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Poliambulatorio Giovanni Paolo II, I-71013 San Giovanni Rotondo (FG), Italy. E-mail: g.merla@operapadrepio.itSearch for more papers by this authorAlexandre Reymond, Corresponding Author Alexandre Reymond Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland These senior authors contributed equally to this work.Correspondence to: Alexandre Reymond, Center for Integrative Genomics, University of Lausanne, Genopode building, 1015 Lausanne, Switzerland. E-mail: alexandre.reymond@unil.ch; Giuseppe Merla, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Poliambulatorio Giovanni Paolo II, I-71013 San Giovanni Rotondo (FG), Italy. E-mail: g.merla@operapadrepio.itSearch for more papers by this author Ali Abdullah Alfaiz, Ali Abdullah Alfaiz Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland These authors contributed equally to this work.Search for more papers by this authorLucia Micale, Lucia Micale Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy These authors contributed equally to this work.Search for more papers by this authorBarbara Mandriani, Barbara Mandriani Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, ItalySearch for more papers by this authorBartolomeo Augello, Bartolomeo Augello Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, ItalySearch for more papers by this authorMaria Teresa Pellico, Maria Teresa Pellico Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, ItalySearch for more papers by this authorJacqueline Chrast, Jacqueline Chrast Center for Integrative Genomics, University of Lausanne, Lausanne, SwitzerlandSearch for more papers by this authorIoannis Xenarios, Ioannis Xenarios Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland Swiss Institute of Bioinformatics (SIB), Lausanne, SwitzerlandSearch for more papers by this authorLeopoldo Zelante, Leopoldo Zelante Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, ItalySearch for more papers by this authorGiuseppe Merla, Corresponding Author Giuseppe Merla Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland PhD Program, Scienze della Riproduzione e dello Sviluppo, University of Trieste, Trieste, Italy These senior authors contributed equally to this work.Correspondence to: Alexandre Reymond, Center for Integrative Genomics, University of Lausanne, Genopode building, 1015 Lausanne, Switzerland. E-mail: alexandre.reymond@unil.ch; Giuseppe Merla, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Poliambulatorio Giovanni Paolo II, I-71013 San Giovanni Rotondo (FG), Italy. E-mail: g.merla@operapadrepio.itSearch for more papers by this authorAlexandre Reymond, Corresponding Author Alexandre Reymond Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland These senior authors contributed equally to this work.Correspondence to: Alexandre Reymond, Center for Integrative Genomics, University of Lausanne, Genopode building, 1015 Lausanne, Switzerland. E-mail: alexandre.reymond@unil.ch; Giuseppe Merla, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Poliambulatorio Giovanni Paolo II, I-71013 San Giovanni Rotondo (FG), Italy. E-mail: g.merla@operapadrepio.itSearch for more papers by this author First published: 11 February 2014 https://doi.org/10.1002/humu.22529Citations: 38 Communicated by Nancy Spinner Contract grant sponsors: The Italian Ministry of Health (Ricerca Corrente 2012–13); The Swiss National Science Foundation; The Swiss NSF Sinergia program; The Simons Foundation Autism Research Initiative; The Lithuanian-Swiss Cooperation Program. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat ABSTRACT 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. Citing Literature Supporting Information Disclaimer: Supplementary materials have been peer-reviewed but not copyedited. Filename Description humu22529-sup-0001-SupMat.pdf142.9 KB Figure S1. RT-PCR semiquantitative analysis of TBC1D7 (lanes 2–6) and GAPDH (lanes 7–11) transcripts in control and proband LCLs. Table S1. Clinical features of TBC1D7 syndrome patients Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume35, Issue4April 2014Pages 447-451 RelatedInformation