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.
Giannandrea
Maila
M
Dulbecco Telethon Institute at Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Bianchi
Veronica
V
Mignogna
Maria Lidia
ML
Sirri
Alessandra
A
Carrabino
Salvatore
S
D'Elia
Errico
E
Vecellio
Matteo
M
Russo
Silvia
S
Cogliati
Francesca
F
Larizza
Lidia
L
Ropers
Hans-Hilger
HH
Tzschach
Andreas
A
Kalscheuer
Vera
V
Oehl-Jaschkowitz
Barbara
B
Skinner
Cindy
C
Schwartz
Charles E
CE
Gecz
Jozef
J
Van Esch
Hilde
H
Raynaud
Martine
M
Chelly
Jamel
J
de Brouwer
Arjan P M
AP
Toniolo
Daniela
D
D'Adamo
Patrizia
P
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