Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly.
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.
Dulbecco Telethon Institute at Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Maila
M
Giannandrea
Veronica
V
Bianchi
Maria Lidia
ML
Mignogna
Alessandra
A
Sirri
Salvatore
S
Carrabino
Errico
E
D'Elia
Matteo
M
Vecellio
Silvia
S
Russo
Francesca
F
Cogliati
Lidia
L
Larizza
Hans-Hilger
HH
Ropers
Andreas
A
Tzschach
Vera
V
Kalscheuer
Barbara
B
Oehl-Jaschkowitz
Cindy
C
Skinner
Charles E
CE
Schwartz
Jozef
J
Gecz
Hilde
H
Van Esch
Martine
M
Raynaud
Jamel
J
Chelly
Arjan P M
AP
de Brouwer
Daniela
D
Toniolo
Patrizia
P
D'Adamo
D000818:Animals; D001321:Autistic Disorder / Q000150:complications* / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D019465:Craniofacial Abnormalities / Q000150:complications* / Q000235:genetics; D004252:DNA Mutational Analysis; D015536:Down-Regulation / Q000235:genetics; D004827:Epilepsy / Q000150:complications* / Q000235:genetics; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000150:complications* / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D010375:Pedigree; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D013569:Synapses / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000235:genetics*
D034741:RNA, Small Interfering; C547812:Rab39B protein, human; D020691:rab GTP-Binding Proteins