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.
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