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|dc.contributor.author||Van Esch, H.||en|
|dc.identifier.citation||American Journal of Human Genetics, 2010; 86(2):185-195||en|
|dc.description.abstract||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.||en|
|dc.description.statementofresponsibility||Maila Giannandrea, Veronica Bianchi, Maria Lidia Mignogna, Alessandra Sirri, Salvatore Carrabino, Errico D'Elia, Matteo Vecellio, Silvia Russo, Francesca Cogliati, Lidia Larizza, Hans-Hilger Ropers, Andreas Tzschach, Vera Kalscheuer, Barbara Oehl-Jaschkowitz, Cindy Skinner, Charles E. Schwartz, Jozef Gecz, Hilde Van Esch, Martine Raynaud, Jamel Chelly, Arjan P.M. de Brouwer, Daniela Toniolo and Patrizia D'Adamo||en|
|dc.publisher||Univ Chicago Press||en|
|dc.rights||Copyright © 2010 The American Society of Human Genetics Published by Elsevier Inc.||en|
|dc.subject||Brain; Neurons; Synapses; Hela Cells; Golgi Apparatus; Animals; Humans; Mice; Craniofacial Abnormalities; Epilepsy; Mental Retardation, X-Linked; rab GTP-Binding Proteins; RNA, Small Interfering; Pedigree; DNA Mutational Analysis; Autistic Disorder; Cell Differentiation; Organ Specificity; Down-Regulation; Base Sequence; Protein Transport; Mutation; Molecular Sequence Data; Female; Male||en|
|dc.title||Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly||en|
|dc.identifier.orcid||Gecz, J. [0000-0002-7884-6861]||en|
|Appears in Collections:||Paediatrics publications|
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