HGNC Approved Gene Symbol: RAB5B
Cytogenetic location: 12q13.2 Genomic coordinates (GRCh38): 12:55,973,949-55,996,683 (from NCBI)
The RAB5B gene encodes a Ras-related GTPase. Along with its paralogous genes RAB5A (179512) and RAB5C (604037), RAB5B also has a noncanonical function in the early endocytic vesicular fusion pathway (summary by Huang et al., 2022). See RAB5A for a more detailed discussion of RAB.
A number of processes in eukaryotic cells are believed to be regulated by small, monomeric GTPases belonging to the RAS superfamily. A subset of these GTPases (the yeast YPTI/SEC4 gene products and their mammalian counterparts, the RAB proteins) plays a central role in membrane trafficking. Each of the several proteins of this subfamily that have been identified is thought to regulate vesicular trafficking at a specific subcellular compartment. Wilson and Wilson (1992) cloned cDNA of a novel member of the RAB family by screening a human umbilical vein endothelial cell cDNA library with oligonucleotide probes corresponding to a region conserved in all RAB proteins. The newly identified RAB protein was 81% identical to human RAB5, the canine counterpart of which had been localized to the plasma membrane and early endosomes. In light of this homology, Wilson and Wilson (1992) called the new member of the GTPase superfamily RAB5B. It is presumably involved in vesicular trafficking at the plasma membrane.
By fluorescence in situ hybridization, Korenberg et al. (1995) mapped the RAB5B gene to 12q13.
Huang et al. (2022) found expression of the RAB5B gene in pulmonary AT2 cells, as well as in other lung cell types. In normal lung tissue, RAB5B colocalized with immature surfactant proteins proSP-B (178640) and proSP-C (178620) as well as the early endosome marker EEA1 (605070). Knockdown of Rab5b in MLE15 cells resulted in a significant reduction in mature SPB from proSB-B, suggesting that RAB5B has an essential role in the regulated secretion pathway of lung surfactant. Further studies indicated that RAB5B also functions in endocytic recycling of extracellular mature surfactant proteins.
Associations Pending Confirmation
For a discussion of a possible association between pulmonary surfactant metabolism dysfunction (see, e.g., SMDP1, 265120) and variation in the RAB5B gene, see 179514.0001.
This variant is classified as a variant of unknown significance because its contribution to pulmonary surfactant metabolism dysfunction (see, e.g., SMDP1, 265120) has not been confirmed.
In a 2-year-old Pakistani girl with global developmental delay, dysmorphic features, and progressive interstitial lung disease due to pulmonary surfactant metabolism dysfunction (SMDP), Huang et al. (2022) identified a de novo heterozygous c.406G-C transversion (c.406G-C, NM_002868.3) in the RAB5B gene, resulting in an asp136-to-his (D136H) substitution at a highly conserved residue in the fourth region of the small GTPase nucleotide binding domain. The variant, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Patient lung tissue showed a significant (80%) reduction in RAB5B immunostaining in AT2 cells compared to controls, which may have resulted from degradation of the aberrant protein. ProSP-B (SFTPB; 178640) and proSP-C (SFTPC; 178620) were present at normal levels in patient AT2 cells, but mature SP-B and SP-C were significantly reduced, indicating a defect in trafficking and impaired processing of surfactant proteins in the vesicular pathway. EEA1 levels were also reduced, consistent with a defect in the early endosomal pathway. The findings were consistent with surfactant dysfunction causing interstitial lung disease in the proband. Generation of the orthologous D135H variant in C. elegans was lethal at the larval stage in the homozygous state. Heterozygous animals showed decreased locomotion and had decreased size compared to controls, with a strong dominant-negative effect. Heterozygous animals had defects in endocytic trafficking; early endosomes were puncta-sized and failed to mature into larger ring-shaped endosomes, suggesting defective early endosome fusion. At age 6 months, the patient showed hypotonia, broad nasal bridge with telecanthus, short squared digits and overlapping toes. She had profound developmental delay with static encephalopathy. At 11 months of age, she developed respiratory insufficiency and digital clubbing associated with diffuse ground-glass opacities on imaging, consistent with interstitial lung disease and suggestive of a surfactant dysfunction disorder. Histology revealed pulmonary alveolar proteinosis, AT2 cell hyperplasia, lobar remodeling, and early fibrosis. Levels of SFTPB were decreased in AT2 cells. She died of respiratory failure at 2 years of age. Variants in known surfactant disorder genes were excluded.
Huang, H., Pan, J., Spielberg, D. R., Hanchard, N. A., Scott, D. A., Burrage, L. C., Dai, H., Murdock, D., Rosenfeld, J. A., Mohammad, A., Huang, T., Lindsey, A. G., and 14 others. A dominant negative variant of RAB5B disrupts maturation of surfactant protein B and surfactant protein C. Proc. Nat. Acad. Sci. 119: e2105228119, 2022. [PubMed: 35121658] [Full Text: https://doi.org/10.1073/pnas.2105228119]
Korenberg, J. R., Chen, X.-N., Adams, M. D., Venter, J. C. Toward a cDNA map of the human genome. Genomics 29: 364-370, 1995. [PubMed: 8666383] [Full Text: https://doi.org/10.1006/geno.1995.9993]
Wilson, D. B., Wilson, M. P. Identification and subcellular localization of human rab5b, a new member of the ras-related superfamily of GTPases. J. Clin. Invest. 89: 996-1005, 1992. [PubMed: 1541686] [Full Text: https://doi.org/10.1172/JCI115683]