HGNC Approved Gene Symbol: RAB7A
SNOMEDCT: 717008005;
Cytogenetic location: 3q21.3 Genomic coordinates (GRCh38): 3:128,726,183-128,814,798 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q21.3 | Charcot-Marie-Tooth disease, type 2B | 600882 | Autosomal dominant | 3 |
RAB7, a member of the RAB family of small GTPases, is a ubiquitously expressed protein that plays a vital role in the regulation of the trafficking, maturation, and fusion of endocytic and autophagic vesicles. RAB7 specifically controls the transition of early endosomes into the late-endosomal/lysosomal system and subsequent degradation of cargos associated with target vesicles. In addition, fusion of autophagic vacuoles with lysosomes requires RAB7 activity (summary by McCray et al., 2010).
Vitelli et al. (1996) cloned a RAB7 cDNA by screening a human placenta cDNA library with a rat Rab7 cDNA. The RAB7 cDNA encodes a 207-amino acid protein whose sequence is 99% identical to those of mouse, rat, and dog Rab7 and 61% identical to that of yeast Rab7. Using Northern blot analysis, Vitelli et al. (1996) found that RAB7 was expressed as 1.7- and 2.5-kb transcripts in all cell lines examined but that there was a large difference in the total amount of RAB7 mRNA among the cell lines.
In studies using antisense RNA, Davies et al. (1997) found that downregulation of RAB7 gene expression in HeLa cells using antisense RNA induces severe cell vacuolation that resembles the phenotype seen in fibroblasts from patients with Chediak-Higashi syndrome (214500).
Edinger et al. (2003) found that, in the presence of growth factor, inhibition of mammalian Rab7 had no effect on nutrient transporter expression in mouse pro-B-lymphocytic cells. In growth factor-deprived cells, however, blocking Rab7 function prevented the clearance of glucose and amino acid transporter proteins from the cell surface. When Rab7 was inhibited, growth factor-deprived cells maintained their mitochondrial membrane potential and displayed prolonged, growth factor-independent, nutrient-dependent cell survival. The authors concluded that RAB7 functions as a proapoptotic protein by limiting cell-autonomous nutrient uptake.
The retromer is a membrane-associated coat complex that functions in the endosomal-to-Golgi retrieval of membrane proteins. The retromer consists of 2 distinct subcomplexes, a cargo-selective subcomplex containing VPS35 (601501), VPS29 (606932), and VPS26 (see 605506), and a subcomplex of sorting nexins, SNX1 (601272) and SNX2 (605929), that tubulates the endosomal membrane. Seaman et al. (2009) found that the VPS35/VPS29/VPS26 subcomplex interacted with RAB7 and required RAB7 for recruitment to endosomes. The subcomplex interacted with a GTP-locked RAB7 mutant, but a GDP-locked RAB7 mutant inhibited VPS26 recruitment to endosomal membranes. Knockdown of RAB7 in HeLa cells redistributed VPS26 and VPS35 from membranes to the cytoplasm and reduced the efficiency of endosome-to-Golgi retrieval of membrane proteins. Seaman et al. (2009) also found that the GTPase-activating protein TBC1D5 (615740) caused dissociation of RAB7 from endosomes and inhibited VPS26 recruitment to endosomal membranes.
Wong et al. (2018) identified the formation and regulation of mitochondria-lysosome membrane contact sites using electron microscopy, structured illumination microscopy, and high spatial and temporal resolution confocal live cell imaging. Mitochondria-lysosome contacts formed dynamically in healthy untreated cells and were distinct from damaged mitochondria that were targeted into lysosomes for degradation. Contact formation was promoted by active GTP-bound lysosomal RAB7, and contact untethering was mediated by recruitment of the RAB7 GTPase-activating protein TBC1D15 (612662) to mitochondria by FIS1 (609003) to drive RAB7 GTP hydrolysis and thereby release contacts. Functionally, lysosomal contacts mark sites of mitochondrial fission, allowing regulation of mitochondrial networks by lysosomes, whereas conversely, mitochondrial contacts regulate lysosomal RAB7 hydrolysis via TBC1D15. Wong et al. (2018) concluded that mitochondria-lysosome contacts thus allow bidirectional regulation of mitochondrial and lysosomal dynamics.
Using a proximity-dependent biotinylation approach in HEK293 cells, followed by immunoprecipitation analysis, Yan et al. (2022) identified C5ORF51 (RIMOC1; 620266) as an interacting partner of RAB7A during mitophagy. As a component of the MON1 (see 611464)-CCZ1 (620660) complex, a RAB7A guanine nucleotide exchange factor (GEF), C5ORF51 interacted with GDP-bound RAB7A and promoted its interaction with the MON1-CCZ1 GEF complex after mitochondrial depolarization during mitophagy. Knockdown analysis in HeLa cells indicated that C5ORF51 was required for clearance of depolarized mitochondria during mitophagy. C5ORF51 was not required for late endocytic trafficking or lysosome activity during mitophagy, but instead was required for RAB7A translocation to depolarized mitochondria and for ATG9A (612204) vesicle recruitment to depolarized mitochondria. In addition, RAB7A protein was dramatically reduced in C5ORF51-deficient cells, because C5ORF51 promoted stability of RAB7A by inhibiting its proteasomal degradation during mitophagy.
Crystal Structure
Rak et al. (2004) reported the crystal structures of REP1 (300390) in complex with monoprenylated or C-terminally truncated RAB7. The structures revealed that RAB7 interacts with the RAB-binding platform of REP1 via an extended interface involving the switch 1 and 2 regions. The C terminus of the REP1 molecule functions as a mobile lid covering a conserved hydrophobic patch on the surface of REP1 that in the complex coordinates the C termini of RAB proteins.
McCray et al. (2010) presented the 2.8-angstrom crystal structure of GTP-bound L129F mutant Rab7 (602298.0001), which revealed an alteration to the nucleotide binding pocket that is predicted to alter GTP binding. Biochemical analysis revealed that disease-associated mutations in Rab7 did not lead to an intrinsic GTPase defect, but permitted unregulated nucleotide exchange leading to both excessive activation and hydrolysis-independent inactivation. Consistent with augmented activity, mutant Rab7 showed significantly enhanced interaction with a subset of effector proteins. Dynamic imaging demonstrated that mutant Rab7 was abnormally retained on target membranes. However, the increased activation of mutant Rab7 was counterbalanced by unregulated, GTP hydrolysis-independent membrane cycling. Disease mutations were able to rescue the membrane cycling of a GTPase-deficient mutant. The authors concluded that disease mutations uncouple Rab7 from the spatial and temporal control normally imposed by regulatory proteins and cause disease not by a gain of novel toxic function, but by misregulation of native Rab7 activity.
Davies et al. (1997) mapped the RAB7 gene to chromosome 3 by PCR analysis of somatic cell hybrid DNAs. Barbosa et al. (1995) mapped the mouse Rab7 gene to chromosome 9 by intersubspecific backcross analysis.
Using fluorescence in situ hybridization and somatic cell hybrid analysis, Kashuba et al. (1997) mapped the RAB7 gene to 3q21.
The inherited neuropathies of the peripheral nervous system show considerable clinical and genetic heterogeneity. Some forms, the ulcero-mutilating neuropathies, are characterized by prominent sensory loss, often complicated by severe infections, arthropathy, and amputations. One form of autosomal dominant ulcero-mutilating neuropathy, Charcot-Marie-Tooth type 2B (CMT2B; 600882), or hereditary motor and sensory neuropathy type IIB, was mapped to 3q13-q22 by Kwon et al. (1995). Verhoeven et al. (2003) demonstrated 2 missense mutations (L129F, 602298.0001; V162M, 602298.0002) in the RAB7 gene, causing the CMT2B phenotype in 3 extended families and in 3 patients with a positive family history. The alignment of RAB7 orthologs showed that both missense mutations targeted highly conserved amino acid residues. Verhoeven et al. (2003) showed that RAB7 is ubiquitously expressed.
In 2 Austrian families and in an Austrian patient with a positive family history, Verhoeven et al. (2003) found that CMT2B (600882) was associated with a 385C-T transition in exon 3 of the RAB7 gene, resulting in a leu129-to-phe (L129F) missense amino acid change. The Austrian families were originally believed to be unrelated and had been reported by Auer-Grumbach et al. (2000) as CMT140 and Auer-Grumbach et al. (2000) as CMT126. However, Verhoeven et al. (2003) determined that a small branch of CMT126 was related to CMT140. The L129F mutation was identified in affected members of CMT140 and affected members of the small branch of CMT126; the remaining affected members of CMT126 did not have the RAB7 mutation and were excluded by linkage analysis from the CMT2B locus, indicating genetic heterogeneity. Those CMT126 members who did have the L129F mutation had the same haplotype as accompanied the mutation in CMT140, indicating a close familial relationship. In CMT126, no obvious differences in neurologic and electrophysiologic findings were detected between patients with the L129F mutation and those without it, except that the phenotype was more severe in the branch with the L129F mutation, including the occurrence of ulcers and amputations. The single Austrian patient with a family history of CMT2B who shared the L129F mutation also shared the associated haplotype with affected members of the other 2 Austrian families, indicating founder effect.
In 2 unrelated families, Verhoeven et al. (2003) observed a 484G-A transition (val162 to met; V162M) in exon 4 of the RAB7 gene as the cause of CMT2B (600882). In an Austrian patient and a Belgian patient with CMT2B, Verhoeven et al. (2003) found the V162M mutation, but these patients did not share the disease haplotype and were not related to the Scottish and American families in which the mutation was found.
In a patient with CMT2B (600882), Houlden et al. (2004) identified a heterozygous A-to-C transversion in exon 4 of the RAB7 gene, resulting in an asn161-to-thr (N161T) substitution in a highly conserved region of the protein. The N161T mutation was not identified in an unaffected brother or in 200 control chromosomes. Sural nerve biopsy from the patient showed a marked decrease in immunostaining for the Rab-interacting lysosomal protein (RILP; 607848), an effector of RAB7, suggesting a possible pathogenic mechanism.
In a 32-year-old man with CMT2B (600882), Meggouh et al. (2006) identified a de novo heterozygous 471G-C transversion in exon 4 of the RAB7 gene, resulting in a lys157-to-asn (K157N) substitution. He had onset of decreased sensation in the feet leading to small injuries at age 12 years. At age 32, he had steppage gait, atrophy of the lower legs and hand muscles, high-arched feet, claw toes, and decreased sensation in the lower limbs.
Seaman et al. (2009) found that RAB7 with the K157N mutation interacted weakly with the cargo-selective retromer subcomplex and reduced association of the retromer subunit VPS26 (605506) with membranes.
Auer-Grumbach, M., De Jonghe, P., Wagner, K., Verhoeven, K., Hartung, H.-P., Timmerman, V. Phenotype-genotype correlations in a CMT2B family with refined 3q13-q22 locus. Neurology 55: 1552-1557, 2000. [PubMed: 11094113] [Full Text: https://doi.org/10.1212/wnl.55.10.1552]
Auer-Grumbach, M., Wagner, K., Timmerman, V., De Jonghe, P., Hartung, H.-P. Ulcero-mutilating neuropathy in an Austrian kinship without linkage to hereditary motor and sensory neuropathy IIB and hereditary sensory neuropathy I loci. Neurology 54: 45-52, 2000. [PubMed: 10636124] [Full Text: https://doi.org/10.1212/wnl.54.1.45]
Barbosa, M. D., Johnson, S. A., Achey, K., Gutierrez, M. J., Wakeland, E. K., Zerial, M., Kingsmore, S. F. The Rab protein family: genetic mapping of six Rab genes in the mouse. Genomics 30: 439-444, 1995. [PubMed: 8825628] [Full Text: https://doi.org/10.1006/geno.1995.1262]
Davies, J. P., Cotter, P. D., Ioannou, Y. A. Cloning and mapping of human Rab7 and Rab9 cDNA sequences and identification of a Rab9 pseudogene. Genomics 41: 131-134, 1997. [PubMed: 9126495] [Full Text: https://doi.org/10.1006/geno.1997.4644]
Edinger, A. L., Cinalli, R. M., Thompson, C. B. Rab7 prevents growth factor-independent survival by inhibiting cell-autonomous nutrient transporter expression. Dev. Cell 5: 571-582, 2003. [PubMed: 14536059] [Full Text: https://doi.org/10.1016/s1534-5807(03)00291-0]
Houlden, H., King, R. H. M., Muddle, J. R., Warner, T. T., Reilly, M. M., Orrell, R. W., Ginsberg, L. A novel RAB7 mutation associated with ulcero-mutilating neuropathy. Ann. Neurol. 56: 586-590, 2004. [PubMed: 15455439] [Full Text: https://doi.org/10.1002/ana.20281]
Kashuba, V. I., Gizatullin, R. Z., Protopopov, A. I., Allikmets, R., Korolev, S., Li, J., Boldog, F., Tory, K., Zabarovska, V., Marcsek, Z., Sumegi, J., Klein, G., Zabarovsky, E. R., Kisselev, L. NotI linking/jumping clones of human chromosome 3: mapping of the TFRC, RAB7 and HAUSP genes to regions rearranged in leukemia and deleted in solid tumors. FEBS Lett. 419: 181-185, 1997. [PubMed: 9428630] [Full Text: https://doi.org/10.1016/s0014-5793(97)01449-x]
Kwon, J. M., Elliott, J. L., Yee, W.-C., Ivanovich, J., Scavarda, N. Charcot-Marie-Tooth type II locus to chromosome 3q. Am. J. Hum. Genet. 57: 853-858, 1995. [PubMed: 7573046]
McCray, B. A., Skordalakes, E., Taylor, J. P. Disease mutations in Rab7 result in unregulated nucleotide exchange and inappropriate activation. Hum. Molec. Genet. 19: 1033-1047, 2010. [PubMed: 20028791] [Full Text: https://doi.org/10.1093/hmg/ddp567]
Meggouh, F., Bienfait, H. M. E., Weterman, M. A. J., de Visser, M., Baas, F. Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene. Neurology 67: 1476-1478, 2006. [PubMed: 17060578] [Full Text: https://doi.org/10.1212/01.wnl.0000240068.21499.f5]
Rak, A., Pylypenko, O., Niculae, A., Pyatkov, K., Goody, R. S., Alexandrov, K. Structure of the Rab7:REP-1 complex: insights into the mechanism of Rab prenylation and choroideremia disease. Cell 117: 749-760, 2004. [PubMed: 15186776] [Full Text: https://doi.org/10.1016/j.cell.2004.05.017]
Seaman, M. N. J., Harbour, M. E., Tattersall, D., Read, E., Bright, N. Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5. J. Cell Sci. 122: 2371-2382, 2009. [PubMed: 19531583] [Full Text: https://doi.org/10.1242/jcs.048686]
Verhoeven, K., De Jonghe, P., Coen, K., Verpoorten, N., Auer-Grumbach, M., Kwon, J. M., FitzPatrick, D., Schmedding, E., De Vriendt, E., Jacobs, A., Van Gerwen, V., Wagner, K., Hartung, H.-P., Timmerman, V. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am. J. Hum. Genet. 72: 722-727, 2003. [PubMed: 12545426] [Full Text: https://doi.org/10.1086/367847]
Vitelli, R., Chiariello, M., Lattero, D., Bruni, C. B., Bucci, C. Molecular cloning and expression analysis of the human Rab7 GTP-ase complementary deoxyribonucleic acid. Biochem. Biophys. Res. Commun. 229: 887-890, 1996. [PubMed: 8954989] [Full Text: https://doi.org/10.1006/bbrc.1996.1897]
Wong, Y. C., Ysselstein, D., Krainc, D. Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature 554: 382-386, 2018. [PubMed: 29364868] [Full Text: https://doi.org/10.1038/nature25486]
Yan, B. R., Li, T., Coyaud, E., Laurent, E. M. N., St-Germain, J., Zhou, Y., Kim, P. K., Raught, B., Brumell, J. H. C5orf51 is a component of the MON1-CCZ1 complex and controls RAB7A localization and stability during mitophagy. Autophagy 18: 829-840, 2022. [PubMed: 34432599] [Full Text: https://doi.org/10.1080/15548627.2021.1960116]