Mutations in the Small GTPase Gene RAB39B Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly

• Published in: American journal of human genetics Vol. 86; no. 2; pp. 185 - 195
• Main 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, Oehl-Jaschkowitz, Barbara, Skinner, Cindy, Schwartz, Charles E., Gecz, Jozef, Van Esch, Hilde, Raynaud, Martine, Chelly, Jamel, de Brouwer, Arjan P.M., Toniolo, Daniela, D'Adamo, Patrizia
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 12.02.2010; Cell Press; Elsevier (Cell Press); Elsevier
• Subjects: Adult and adolescent clinical studies; Animals; Autism; Autistic Disorder - complications; Autistic Disorder - genetics; Base Sequence; Biochemistry, Molecular Biology; Biological and medical sciences; Brain - metabolism; Brain - pathology; Cell Differentiation; Craniofacial Abnormalities - complications; Craniofacial Abnormalities - genetics; DNA Mutational Analysis; Down-Regulation - genetics; Epilepsy; Epilepsy - complications; Epilepsy - genetics; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Golgi Apparatus - metabolism; HeLa Cells; Humans; Intellectual deficiency; Intellectual disabilities; Life Sciences; Male; Medical genetics; Medical sciences; Mice; Molecular and cellular biology; Molecular Sequence Data; Mutation; Mutation - genetics; Neurons - metabolism; Neurons - pathology; Organ Specificity - genetics; Pediatrics; Pedigree; Protein Transport; Proteins; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; rab GTP-Binding Proteins - genetics; RNA, Small Interfering - metabolism; Synapses - genetics; X-Linked Intellectual Disability - complications; X-Linked Intellectual Disability - genetics; Human; Sex linked character; Nervous system diseases; Enzyme; Triphosphoric monoester hydrolases; Epilepsy; dGTPase; Esterases; Developmental disorder; Mental retardation; Cerebral disorder; Genetic disease; Autism; Gene; Central nervous system disease; Intellectual deficiency; Hydrolases; Genetics; X-Chromosome; Mutation; Neurological disorder; Macrocephaly
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2010.01.011

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.