Alternative titles; symbols
HGNC Approved Gene Symbol: VPS53
Cytogenetic location: 17p13.3 Genomic coordinates (GRCh38): 17:508,668-714,839 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.3 | Pontocerebellar hypoplasia, type 2E | 615851 | Autosomal recessive | 3 |
VPS53 is a part of the Golgi-associated retrograde protein complex (GARP), which is involved in retrograde transport of early and late endosomes to the late Golgi. GARP proteins interact with RAB proteins (e.g., RAB6A; 179513) and SNARE proteins (e.g., STX6; 603944) (Liewen et al., 2005). VPS53 is also a component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane (Schindler et al., 2015).
By searching databases for homologs of yeast Vps53, Liewen et al. (2005) identified human VPS53. The full-length human protein contains N-terminal coiled-coil domains. The authors also identified a splice variant encoding an isoform that lacks amino acids 96 to 124. Immunofluorescence microscopy of COS-7 cells showed that Vps52 (603443), Vps53, and Vps54 (614633) expression overlapped with the Golgi protein Gm130 (GOLGA2; 602580) in a polarized perinuclear area and with the endosome markers Mpr (see IGF2R, 147280) and Tfr (190010) at the perinuclear envelope. Subcellular fractionation experiments in canine cells detected the 3 VPS proteins in the smooth membrane/Golgi fraction, but not in the cytosol.
By coimmunoprecipitation analysis, Liewen et al. (2005) found that human VPS53 interacted with human VPS52 and VPS54. RAB6B (615852) and the short isoform of STX10 (603765) immunoprecipitated VPS52, but not VPS53 or VPS54.
Using a large-scale small interfering RNA screen to identify host factors required by human immunodeficiency virus (HIV)-1 (see 609423), Brass et al. (2008) identified more than 250 HIV-dependency factors (HDFs), 79 of which showed significantly higher expression in immune tissues compared with other tissues. The HDFs RAB6 and VPS53, retrograde Golgi transport proteins, were involved in viral entry. Brass et al. (2008) proposed that targeting of HDFs essential for the viral cycle but not critical for the host may avoid drug resistance due to viral diversity and escape mutation.
Using biochemical and protein interaction assays, Schindler et al. (2015) found that 3 GARP complex components, ANG2 (VPS51; 615738), VPS52, and VPS53, formed a distinct complex, termed the EARP complex, with syndetin (VPS50; 616465) substituting for the GARP component VPS54. The 4 EARP components interacted in a 1:1:1:1 ratio. Syndetin did not interact with VPS54, but yeast 2-hybrid analysis showed that both syndetin and VPS54 preferentially interacted with VPS53. Knockdown of any protein in the EARP complex in HeLa cells via small interfering RNA reduced the amounts of all other complex components. Confocal immunofluorescence microscopy of rat hippocampal neurons expressing tagged proteins and live-cell imaging of transfected HeLa cells showed that syndetin determined localization of the EARP complex to RAB4A (179511)-positive recycling endosomes, whereas VPS54 determined localization of the GARP complex to the trans-Golgi network. Functional analyses suggested that the EARP complex promoted recycling of internalized transferrin receptor (TFRC; 190010) to the cell surface. Schindler et al. (2015) concluded that the EARP complex is involved in canonical membrane fusion events in the process of endocytic recycling.
Gross (2014) mapped the VPS53 gene to chromosome 17p13.3 based on an alignment of the VPS53 sequence (GenBank BC029560) with the genomic sequence (GRCh37).
In 10 affected individuals from 4 nonconsanguineous families of Jewish Moroccan descent with pontocerebellar hypoplasia type 2E (PCH2E; 615851), Feinstein et al. (2014) identified compound heterozygous mutations in the VPS53 gene (615850.0001 and 615850.0002). The mutations were found by a combination of genomewide linkage analysis and whole-exome sequencing. The patients had profound mental retardation with essentially no developmental milestones, progressive microcephaly, spastic quadriplegia, and early-onset seizures. Although patient fibroblasts showed CD63 (155740)-positive swollen vesicles, suggesting disruption of the GARP complex, there was no evidence of a lysosomal storage disorder.
In 10 affected individuals from 4 nonconsanguineous families of Jewish Moroccan descent with pontocerebellar hypoplasia type 2E (PCH2E; 615851), including 2 families previously reported by Ben-Zeev et al. (2003), Feinstein et al. (2014) identified compound heterozygous mutations in the VPS53 gene: a c.2084A-G transition in exon 19, resulting in a gln695-to-arg (Q695R) substitution at a highly conserved residue in the second helix of the surface of the C terminus, and a G-to-A transition in intron 14 (c.1556+5G-A; 615850.0002), resulting in a splice site mutation. The mutations, which were found by a combination of genomewide linkage analysis and whole-exome sequencing, were filtered against the dbSNP and 1000 Genomes Project databases. The mutations segregated with the disorder in the families. The Q695R substitution occurs at a highly conserved residue in the second helix of the surface of the C terminus. Study of patient lymphocytes suggested that the splice site mutation was either subject to nonsense-mediated mRNA decay or resulted in a truncated protein. Of Jewish Moroccan controls tested, 2 of 143 carried the missense mutation and 2 of 156 carried the splice site mutation, yielding a carrier frequency of 1 in 37 for each of the mutations in this population, consistent with a founder effect.
In 2 sibs of Moroccan-Jewish origin with PCH2E, Hady-Cohen et al. (2018) identified compound heterozygosity for the Q695R mutation and the c.1556+5G-A mutation. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
For discussion of the c.1556+5G-A transition in the VPS53 gene that was found in compound heterozygous state in patients with PCH2E (615851) by Feinstein et al. (2014), see 615850.0001.
Ben-Zeev, B., Hoffman, C., Lev, D., Watemberg, N., Malinger, G., Brand, N., Lerman-Sagie, T. Progressive cerebellocerebral atrophy: a new syndrome with microcephaly, mental retardation, and spastic quadriplegia. J. Med. Genet. 40: e96, 2003. Note: Electronic Article. [PubMed: 12920088] [Full Text: https://doi.org/10.1136/jmg.40.8.e96]
Brass, A. L., Dykxhoorn, D. M., Benita, Y., Yan, N., Engelman, A., Xavier, R. J., Lieberman, J., Elledge, S. J. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319: 921-926, 2008. [PubMed: 18187620] [Full Text: https://doi.org/10.1126/science.1152725]
Feinstein, M., Flusser, H., Lerman-Sagie, T., Ben-Zeev, B., Lev, D., Agamy, O., Cohen, I., Kadir, R., Sivan, S., Leshinsky-Silver, E., Markus, B., Birk, O. S. VPS53 mutations cause progressive cerebello-cerebral atrophy type 2 (PCCA2). J. Med. Genet. 51: 303-308, 2014. [PubMed: 24577744] [Full Text: https://doi.org/10.1136/jmedgenet-2013-101823]
Gross, M. B. Personal Communication. Baltimore, Md. 6/18/2014.
Hady-Cohen, R., Ben-Pazi, H., Adir, V., Yosovich, K., Blumkin, L., Lerman-Sagie, T., Lev, D. Progressive cerebello-cerebral atrophy and progressive encephalopathy with edema, hypsarrhythmia and optic atrophy may be allelic syndromes. Europ. J. Paediat. Neurol. 22: 1133-1138, 2018. [PubMed: 30100179] [Full Text: https://doi.org/10.1016/j.ejpn.2018.07.003]
Liewen, H., Meinhold-Heerlein, I., Oliveira, V., Schwarzenbacher, R., Luo, G., Wadle, A., Jung, M., Pfreundschuh, M., Stenner-Liewen, F. Characterization of the human GARP (Golgi associated retrograde protein) complex. Exp. Cell Res. 306: 24-34, 2005. [PubMed: 15878329] [Full Text: https://doi.org/10.1016/j.yexcr.2005.01.022]
Schindler, C., Chen, Y., Pu, J., Guo, X., Bonifacino, J. S. EARP is a multisubunit tethering complex involved in endocytic recycling. Nature Cell Biol. 17: 639-650, 2015. [PubMed: 25799061] [Full Text: https://doi.org/10.1038/ncb3129]