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

Dulbecco Telethon Institute at Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2010; 86(2):185-95. DOI: 10.1016/j.ajhg.2010.01.011
Source: PubMed


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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Available from: Cindy Skinner, Oct 10, 2015
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    • "Among the XLID genes identified until now, loss of function mutations in RAB39B lead to ID associated with ASD (Giannandrea et al., 2010; Vissers et al., 2010). We showed that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that localize to the Golgi compartment. "
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    ABSTRACT: A RAS-related class of small monomeric G proteins, the RAB GTPases, is emerging as of key biological importance in compartment specific directional control of vesicles formation, transport and fusion. Thanks to human genetic observation and to the consequent dedicated biochemical work, substantial progress has been made on the understanding of the role played by RAB GTPases and their effector proteins on neuronal development and the shaping of cognitive functions. This review is highlighting these initial elements to broaden the current scope of research on developmental cognitive deficits and take the point of view of RAB GTPases control on membrane transport in neurons and astrocytes.
    Neuroscience & Biobehavioral Reviews 01/2014; 46. DOI:10.1016/j.neubiorev.2013.12.009 · 8.80 Impact Factor
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    • "We also found that UVRAG and Atg14L are immunoprecipitated with Rab39a, suggesting that Rab39a does not interfere the interaction of UVRAG or Atg14L with Beclin1. Rab39a and Rab39b have highly sequence similarities, but their subcellular localization is different; Rab39a and Rab39b localizes to lysosomes (Figure 1) and the Golgi complex [33], respectively. We examined the localization of Rab39a and Rab39b with GM130, a Golgi-marker protein [48] in Raw264.7 macrophages and found that Rab39b overlaps where GM130 localizes, whereas Rab39a shows the localization distinct from this region (Figures S9 and S10). "
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    ABSTRACT: Rab39a has pleiotropic functions in phagosome maturation, inflammatory activation and neuritogenesis. Here, we characterized Rab39a function in membrane trafficking of phagocytosis and autophagy induction in macrophages. Rab39a localized to the periphery of LAMP2-positive vesicles and showed the similar kinetics on the phagosome to that of LAMP1. The depletion of Rab39a did not influence the localization of LAMP2 to the phagosome, but it augments the autophagosome formation and LC3 processing by lipopolysaccharide (LPS) stimulation. The augmentation of autophagosome formation in Rab39a-knockdown macrophages was suppressed by Atg5 depletion or an inhibitor for phosphatidylinostol 3-kinase (PI3K). Immunoprecipitation analysis revealed that Rab39a interacts with PI3K and that the amino acid residues from 34(th) to 41(st) in Rab39a were indispensable for this interaction. These results suggest that Rab39a negatively regulates the LPS-induced autophagy in macrophages.
    PLoS ONE 12/2013; 8(12):e83324. DOI:10.1371/journal.pone.0083324 · 3.23 Impact Factor
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    • "Thus, one may speculate that some of FAM69s may embody the yet unidentified kinases regulating of ER-to-Golgi vesicle transport [67,2011,H89]. It is recognised that vesicular trafficking is critical in neuron development and its malfunctions may result in mental retardation [68]. Thus, the neurological disorders related to FAM69 genes may have a common denominator, malfunction of the secretory pathway in neurons [19]. "
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    ABSTRACT: The catalogues of protein kinases, the essential effectors of cellular signaling, have been charted in Metazoan genomes for a decade now. Yet, surprisingly, using bioinformatics tools, we predicted protein kinase structure for proteins coded by five related human genes and their Metazoan homologues, the FAM69 family. Analysis of three-dimensional structure models and conservation of the classic catalytic motifs of protein kinases present in four out of five human FAM69 proteins suggests they might have retained catalytic phosphotransferase activity. An EF-hand Ca(2+)-binding domain in FAM69A and FAM69B proteins, inserted within the structure of the kinase domain, suggests they may function as Ca(2+)-dependent kinases. The FAM69 genes, FAM69A, FAM69B, FAM69C, C3ORF58 (DIA1) and CXORF36 (DIA1R), are by large uncharacterised molecularly, yet linked to several neurological disorders in genetics studies. The C3ORF58 gene is found deleted in autism, and resides in the Golgi. Unusually high cysteine content and presence of signal peptides in some of the family members suggest that FAM69 proteins may be involved in phosphorylation of proteins in the secretory pathway and/or of extracellular proteins.
    PLoS ONE 06/2013; 8(6):e66427. DOI:10.1371/journal.pone.0066427 · 3.23 Impact Factor
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