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

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.

Identification of a microdeletion at Xp22.13 in a Taiwanese family presenting with Nance-Horan syndrome

“…Alterations in signaling pathways involving the Rho family of small GTPases contribute to syndromic and nonsyndromic mental retardation, 17 and mutations in the small GTPase gene RAB39B (OMIM300774) were also identified in two patients with mental retardation. 18 In this study, magnetic resonance imaging analysis did not reveal structural abnormalities in the brain of these two brothers. Furthermore, the brothers' normal electroencephalograms and lack of history of seizures indicate that this microdeletion does not affect the development of gross brain structure and does not cause epilepsy.…”

An atlas of tissue-specific conserved coexpression for functional annotation and disease gene prediction

“…Indeed, while the manuscript was in preparation, we realized that RAB39B had just been discovered as an actual XLMR gene. 31 Moreover, during the revision process, the GSPT2 gene had been proposed independently as a strong XLMR candidate by a copy-number variation study. 32 We think that the case of USP9X illustrates particularly well the potential usefulness of our approach for selecting the most promising candidates and making hypothesis about their functional interactions with the validated genes.…”

Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis

“…REPS2 is associated with a small G protein and shows strong expression in brain tissue (LSBM, http://www.lsbm.org/index.html). As alterations in signaling pathways involving the Rho family of small GTPases contribute to both syndromic and nonsyndromic MR disorders 36 and mutation in the small GTPase gene RAB39B (OMIM300774) were identified in two MR patients, 37 it is possible that deregulated expression of REPS2 contributes to MR. Protein-truncation mutations in NHS have been identified in patients with Nance-Horan syndrome (OMIM 302350), an X-linked developmental disorder characterized by congenital cataracts, dental anomalies, facial dysmorphism and MR in some cases. As our patients in both families did not have cataracts or dental anomalies, the genomic rearrangement involved in NHS may not affect the function of this gene.…”