Alternative titles; symbols
HGNC Approved Gene Symbol: RAB39B
SNOMEDCT: 716107009;
Cytogenetic location: Xq28 Genomic coordinates (GRCh38) : X:155,258,235-155,264,491 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | Intellectual developmental disorder, X-linked 72 | 300271 | X-linked recessive | 3 |
| Waisman syndrome | 311510 | X-linked recessive | 3 |
RAB proteins, such as RAB39B, are small GTPases involved in the regulation of vesicular trafficking between membrane compartments (Cheng et al., 2002).
During large-scale sequencing of a human fetal brain cDNA library, Cheng et al. (2002) cloned RAB39B. The deduced 213-amino acid protein has a calculated molecular mass of 24 kD. RAB39B contains 4 domains involved in GTP/GDP binding, 5 RabF domains predicted to interact with regulatory proteins, and a C-terminal prenylation motif (xxCxC). Expression of RAB39B in 16 human tissues was below the level of detection by Northern blot analysis, but PCR analysis detected RAB39B in all tissues examined except heart and liver.
Wilson et al. (2014) found colocalization of endogenous RAB39B with markers of the vesicular transport pathway, particularly the early endosome, in mouse and human neuroblastoma cells.
Cheng et al. (2002) determined that the RAB39B gene contains 2 exons and spans about 3.8 kb.
By genomic sequence analysis, Cheng et al. (2002) mapped the RAB39B gene to chromosome Xq28.
Giannandrea et al. (2010) demonstrated expression of the RAB39B gene in human and mouse brain, with significantly increased expression during postnatal development and in adults compared to fetuses. The highest expression was in neuronal precursors and neurons in the hippocampus. Studies in mouse cells showed Rab39b localization to the Golgi apparatus and colocalization with markers that cycle from the cell surface to the trans-Golgi network via sorting and recycling endosomes, suggesting a role in vesicular transport. Downregulation of Rab39b gene in mouse primary hippocampal neurons resulted in decreased numbers of growth cones at neurite terminals and decreased numbers of neuronal branches, indicating disorganized growth. Further studies suggested that decreased neurite extension may lead to defective synapse formation or instability.
Vanmarsenille et al. (2014) demonstrated that overexpression of the Rab39b gene in mouse primary hippocampal neurons resulted in a significant decrease in neuronal branching as well as a decrease in the number of synapses compared to controls. These findings suggested that increased dosage of the RAB39B gene may cause disturbed neuronal development leading to cognitive impairment in humans (see 300815).
Wilson et al. (2014) found that mouse hippocampal neurons transduced with short hairpin RNA (shRNA) against Rab39b had 30% lower density of alpha-synuclein (SNCA; 163890)-immunoreactive puncta in dendritic processes compared to controls. Immunoblot analysis of these cells confirmed a 40% reduction of Rab39b and a 50% reduction of SNCA. The findings suggested that downregulation of RAB39B results in dysregulation of SNCA homeostasis.
Using yeast 2-hybrid assays, Mori et al. (2013) identified mouse Uaca (612516) as a Rab39a (619558)- and Rab39b-binding protein, with the C-terminal coiled-coil domain of Uaca functioning as the binding domain. Immunofluorescence analysis showed that Uaca colocalized with Rab39a or Rab39b in dot-like structures outside of the Golgi when coexpressed in COS-7 cells. In contrast with knockdown of Rab39a in Neuro2A mouse neuroblastoma cells, which altered retinoic acid (RA)-induced neurite morphology, knockdown of Rab39b had no effect.
X-Linked Intellectual Developmental Disorder 72
In 2 unrelated families with X-linked intellectual developmental disorder (XLID72; 300271), Giannandrea et al. (2010) identified 2 different hemizygous mutations in the RAB39B gene (300774.0001-300774.0002) that segregated with the disorder.
Waisman Syndrome
In affected members of the family from Wisconsin with Waisman syndrome (WSMN; 311510) previously reported by Laxova et al. (1985), Wilson et al. (2014) identified a hemizygous missense mutation in the RAB39B gene (T168K; 300774.0003), resulting in destabilization and increased turnover of the mutant protein, consistent with a loss of function. The disorder was characterized by delayed psychomotor development, intellectual disability, and early-onset Parkinson disease. In vitro cellular studies showed that loss of RAB39B was associated with reduced steady-state levels of alpha-synuclein. Wilson et al. (2014) concluded that dysregulation of SNCA homeostasis and defects in vesicular trafficking resulted in the manifestations of this neurologic disorder. Mutations in the RAB39B gene were not found in 187 individuals with early-onset Parkinson disease or in 48 males with neurodegeneration with brain iron accumulation (see, e.g., NBIA1, 234200).
Mata et al. (2015) identified a large pedigree segregating X-linked dominant Parkinson disease. The 7 affected individuals comprised 5 males and 2 females; 2 of the 5 males had intellectual disability. All affected individuals carried a missense mutation in the RAB39B gene (G192R; 300774.0004). Three unaffected females, aged 40, 55, and 86 years, as well as a 41-year-old unaffected male, also carried the mutation. Mata et al. (2015) subsequently screened 587 familial Parkinson disease cases and identified 1 missense and 1 in-frame single-nucleotide deletion. These mutations were predicted to be deleterious in silico but could not be assessed in the families.
Yuan et al. (2015) sequenced the RAB39B gene in 502 Han Chinese patients from mainland China and found no pathogenic mutation or variant in the coding regions or intron-exon boundaries of the gene.
Lochte et al. (2016) sequenced the RAB39B gene, including all introns and intron-exon boundaries, in 552 Parkinson disease patients including 330 males. Patients were mostly of German origin but also included 8 Filipinos. Mean age of onset was 50.9 +/- 15.3 years, and family history was positive in 22.2%. None of the pedigrees suggested X-linked inheritance. Lochte et al. (2016) also sequenced 91 Filipinos with X-linked dystonia-parkinsonism (XDP; 314250), 8 Filipinos with XDP phenotype who did not carry the XDP haplotype, and 186 German controls for variants in RAB39B. They identified 3 variants (1 synonymous, 2 intronic), for which evidence for pathogenicity was inconclusive. Noting that their findings combined with those of Yuan et al. (2015) showed no convincing mutation in RAB39B in more than 1,000 Parkinson disease patients, Lochte et al. (2016) concluded that RAB38B mutations in classic Parkinson disease patients without intellectual disability and without clear X-linked inheritance are rare and do not need to be included in genetic testing.
In affected members of a family with X-linked intellectual developmental disorder-72 (XLID72; 300271) reported by Russo et al. (2000), Giannandrea et al. (2010) identified a G-to-A transition in the 5-prime splice junction of intron 1 of the RAB39B gene. Immunoblotting of HeLa cells transfected with the mutant cDNA did not detect any mutant protein, consistent with a loss of function. The mutation was not found in 150 control chromosomes. In addition to mental retardation, 3 affected individuals had seizures and 1 had autism spectrum disorder.
In affected members of a family with X-linked intellectual developmental disorder-72 (XLID72; 300271), Giannandrea et al. (2010) identified a 21C-A transversion in the RAB39B gene, resulting in a tyr7-to-ter (Y7X) substitution. Immunoblotting of HeLa cells transfected with the mutant cDNA did not detect any mutant protein, consistent with a loss of function. The mutation was not found in 150 control chromosomes. In addition to mental retardation, all 6 affected males had macrocephaly, 1 had obesity, and 2 had autism.
In affected members of a family from Wisconsin with Waisman syndrome (WSMN; 311510), previously reported by Laxova et al. (1985), Wilson et al. (2014) identified a hemizygous c.503C-A transversion in the RAB39B gene, resulting in a thr168-to-lys (T168K) substitution at a conserved residue. The mutation, which was found by direct sequencing of the RAB39B gene, segregated with the disorder in the family. It was not present in the dbSNP (build 137) or Exome Sequencing Project (ESP6500) databases or in 200 control individuals. Expression of the mutation in neuroblastoma cells resulted in low levels of the mutant protein due to rapid turnover, suggesting that the altered protein is destabilized and that the mutation causes a loss of function.
Mata et al. (2015) reported a large US family of European origin in which 7 individuals, 5 males and 2 females, were affected with Parkinson disease; 2 of the males also had mild intellectual disability (WSMN; 311510). Affected individuals had a G-to-A substitution at nucleotide c.574 of the RAB39B gene (c.574G-A, NM_171998.2) resulting in a glycine-to-arginine substitution at codon 192 (G192R). This variant was also found in 3 unaffected females, aged 40, 55, and 86 years, and in an unaffected male, aged 41 years. Among affected individuals, Parkinson disease with classic features had onset at ages 55 and 57 years in the females and between ages 29 and 53 years in the males. Functional studies showed that the mutation resulted in mislocalization of the RAB39B protein, with significantly reduced localization of mutant protein to the plasma membrane compared to wildtype. As the G192R mutation occurs in the hypervariable C-terminal domain (HVD), which mediates intracellular targeting, Mata et al. (2015) suggested that the mutation may disrupt targeting by inhibiting binding to effector molecules. This variant was not identified among 87,725 X chromosomes in the ExAC database.
Cheng, H., Ma, Y., Ni, X., Jiang, M., Guo, L., Ying, K., Xie, Y., Mao, Y. Isolation and characterization of a human novel RAB (RAB39B) gene. Cytogenet. Genome Res. 97: 72-75, 2002. [PubMed: 12438742] [Full Text: https://doi.org/10.1159/000064047]
Giannandrea, M., Bianchi, V., Mignogna, M. L., Sirri, A., Carrabino, S., D'Elia, E., Vecellio, M., Russo, S., Cogliati, F., Larizza, L., Ropers, H.-H., Tzschach, A., and 11 others. Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am. J. Hum. Genet. 86: 185-195, 2010. [PubMed: 20159109] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.011]
Laxova, R., Brown, E. S., Hogan, K., Hecox, K., Opitz, J. M. An X-linked recessive basal ganglia disorder with mental retardation. Am. J. Med. Genet. 21: 681-689, 1985. [PubMed: 4025396] [Full Text: https://doi.org/10.1002/ajmg.1320210409]
Lochte, T., Bruggemann, N., Vollstedt, A.-J., Krause, P., Domingo, A., Rosales, R., Lee, L. V., Hopfner, F., Westenberger, A., Kuhn, A., Klein, C., Lohmann, K. RAB39B mutations are a rare finding in Parkinson disease patients. Parkinsonism Relat. Disord. 23: 116-117, 2016. [PubMed: 26739247] [Full Text: https://doi.org/10.1016/j.parkreldis.2015.12.014]
Mata, I. F., Jang, Y., Kim, C.-H., Hanna, D. S., Dorschner, M. O., Samii, A., Agarwal, P., Roberts, J. W., Klepitskaya, O., Shprecher, D. R., Chung, K. A., Factor, S. A., and 14 others. The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease. Molec. Neurodegener. 10: 50, 2015. Note: Electronic Article. [PubMed: 26399558] [Full Text: https://doi.org/10.1186/s13024-015-0045-4]
Mori, Y., Matsui, T., Omote, D., Fukuda, M. Small GTPase Rab39A interacts with UACA and regulates the retinoic acid-induced neurite morphology of Neuro2A cells. Biochem. Biophys. Res. Commun. 435: 113-119, 2013. [PubMed: 23624502] [Full Text: https://doi.org/10.1016/j.bbrc.2013.04.051]
Russo, S., Cogliati, F., Cavalleri, F., Cassitto, M. G., Giglioli, R., Toniolo, D., Casari, G., Larizza, L. Mapping to distal Xq28 of nonspecific X-linked mental retardation MRX72: linkage analysis and clinical findings in a three-generation Sardinian family. Am. J. Med. Genet. 94: 376-382, 2000. [PubMed: 11050621] [Full Text: https://doi.org/10.1002/1096-8628(20001023)94:5<376::aid-ajmg6>3.0.co;2-a]
Vanmarsenille, L., Giannandrea, M., Fieremans, N., Verbeeck, J., Belet, S., Raynaud, M., Vogels, A., Mannik, K., Ounap, K., Jacqueline, V., Briault, S., Van Esch, H., D'Adamo, P., Froyen, G. Increased dosage of RAB39B affects neuronal development and could explain the cognitive impairment in male patients with distal Xq28 copy number gains. Hum. Mutat. 35: 377-383, 2014. [PubMed: 24357492] [Full Text: https://doi.org/10.1002/humu.22497]
Wilson, G. R., Sim, J. C. H., McLean, C., Giannandrea, M., Galea, C. A., Riseley, J. R., Stephenson, S. E. M., Fitzpatrick, E., Haas, S. A., Pope, K., Hogan, K. J., Gregg, R. G., and 21 others. Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with alpha-synuclein pathology. Am. J. Hum. Genet. 95: 729-735, 2014. [PubMed: 25434005] [Full Text: https://doi.org/10.1016/j.ajhg.2014.10.015]
Yuan, L., Deng, X., Song, Z., Yang, Z., Ni, B., Chen, Y., Deng, H. Genetic analysis of the RAB39B gene in Chinese Han patients with Parkinson's disease. Neurobiol. Aging 36: 2907e11, 2015. Note: Electronic Article. [PubMed: 26163985] [Full Text: https://doi.org/10.1016/j.neurobiolaging.2015.06.019]