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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents

ID: 532611.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly.
Authors:Giannandrea, Maila; Bianchi, Veronica; Mignogna, Maria Lidia; Sirri, Alessandra; Carrabino, Salvatore; D'Elia, Errico; Vecellio, Matteo; Russo, Silvia; Cogliati, Francesca; Larizza, Lidia; Ropers, Hans-Hilger; Tzschach, Andreas; Kalscheuer, Vera M.; Oehl-Jaschkowitz, Barbara; Schwartz, Charles E.; Gecz, Jozef; Van Esch, Hilde; Raynaud, Martine; Chelly, Jamel; de Brouwer, Arjan P.M.; Toniolo, Daniela; D'Adamo, Patrizia
Research Context:This work was supported by funding from Telethon, Italy (TCP04015 to P.D.). M.G. is supported by a fellowship from the Italian Ministry of Research and Health (PRIN 2007). V.B. is supported by a Ph.D. fellowship from Vita Salute San Raffaele University, Milan, Italy. This study was also supported, in part, by grants from the National Institute of Child Health and Human Development (HD26202 to C.E.S.) and the South Carolina Department of Disabilities and Special Needs.
Date of Publication (YYYY-MM-DD):2010-02-12
Title of Journal:The American Journal of Human Genetics
Journal Abbrev.:Am J Hum Genet
Issue / Number:2
Start Page:185
End Page:195
Copyright:© 2010 The American Society of Human Genetics.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Human Mental Retardation (MR) is a common and highly heterogeneous pediatric disorder affecting around 3% of the general population; at least 215 X-linked MR (XLMR) conditions have been described, and mutations have been identified in 83 different genes, encoding proteins with a variety of function, such as chromatin remodeling, synaptic function, and intracellular trafficking. The small GTPases of the RAB family, which play an essential role in intracellular vesicular trafficking, have been shown to be involved in MR. We report here the identification of mutations in the small GTPase RAB39B gene in two male patients. One mutation in family X (D-23) introduced a stop codon seven amino acids after the start codon (c.21C > A; p.Y7X). A second mutation, in the MRX72 family, altered the 5′ splice site (c.215+1G > A) and normal splicing. Neither instance produced a protein. Mutations segregate with the disease in the families, and in some family members intellectual disabilities were associated with autism spectrum disorder, epileptic seizures, and macrocephaly. We show that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that is localized to the Golgi compartment. Its downregulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance. Our results demonstrate developmental and functional neuronal alteration as a consequence of downregulation of RAB39B and emphasize the critical role of vesicular trafficking in the development of neurons and human intellectual abilities.
Comment of the Author/Creator:Email: p.dadamo@hsr.it
15Present address: Department of Experimental Oncology, European Institute of Oncology, 20139 Milan, Italy
16Present address: Vascular Biology and Gene Therapy Laboratory, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Dulbecco Telethon Institute at Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy;
2.Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy;
3.Molecular Genetics Laboratory, Istituto Auxologico Italiano, 20145 Milan, Italy;
4.Chirurgia e Odontoiatria Università di Milano Polo Osp. San Paolo, 20142 Milan, Italy;
5.Practice of Human Genetics, 66424 Homburg (Saar), Germany;
6.J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA;
7.SA Pathology, Women's and Children's Hospital, North Adelaide, SA 5006, Australia;
8.Department of Paediatrics, University of Adelaide, 5006 Adelaide, Australia;
9.Center for Human Genetics, University Hospital Leuven, 3000 Leuven, Belgium;
10.Centre Hospitalier Régional Universitaire de Tours, Service de Génétique and INSERM, U930, 37044 Tours, France;
11Université Paris Descartes; Institut Cochin; INSERM, U567; and Centre National de la Recherche Scientifique, UMR 8104, 75014 Paris, France;
12.Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, 6500 Nijmegen, The Netherlands;
13.Institute of Molecular Genetics-CNR, 20182 Pavia, Italy.
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