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VPS16 CORE SUBUNIT OF CORVET AND HOPS COMPLEXES; VPS16

VPS16 CORE SUBUNIT OF CORVET AND HOPS COMPLEXES; VPS16

Alternative titles; symbolsVACUOLAR PROTEIN SORTING 16, YEAST, HOMOLOG OFHGNC Approved Gene Symbol: VPS16Cytogenetic location: 20p13 Genomic coordinates (GRC...

Alternative titles; symbols

  • VACUOLAR PROTEIN SORTING 16, YEAST, HOMOLOG OF

HGNC Approved Gene Symbol: VPS16

Cytogenetic location: 20p13 Genomic coordinates (GRCh38): 20:2,840,744-2,866,731 (from NCBI)

▼ Description
The VPS16 gene encodes a component of the homotypic fusion and vacuole protein sorting (HOPS) complex, which is involved in endosomal-lysosome and autophagosome-lysosome fusion (summary by Steel et al., 2020).

In yeast, Vps proteins are involved in the trafficking of endocytic and biosynthetic proteins to the vacuole, which functionally resembles the lysosome of higher organisms. Mutations in class C Vps proteins, which includes Vps16, result in the most severe vacuolar protein sorting and morphology defects (Huizing et al., 2001).

▼ Cloning and Expression
By searching an EST database for sequences similar to yeast and Drosophila Vps16, followed by 3-prime and 5-prime RACE, Huizing et al. (2001) cloned VPS16. The deduced 839-amino acid protein has a calculated molecular mass of 94.7 kD. VPS16 shares 24% amino acid identity with yeast Vps16. ESTs sharing significant similarity were also detected in bovine, rat, and mouse databases. Northern blot analysis detected a 3.0-kb VPS16 mRNA in all tissues examined, with highest expression in liver and lowest expression in lung.

▼ Mapping
Huizing et al. (2001) stated that the VPS16 gene maps to chromosome 20p13.

▼ Gene Function
Using an in vitro decapping assay, Zhang et al. (1999) identified yeast Vps16 as a factor involved in regulation of decapping activity in the decay of mRNAs. Mutations in the Vps16 gene resulted in reduction of decapping activity in vitro and in stabilization of both wildtype and nonsense codon-containing mRNAs in vivo. Mutation in the Vps16 gene did not affect expression of the decapping enzyme Dcp1 (see 106180), but it led to inhibition of Dcp1 decapping activity by a component activated in the Vps16 mutant yeast strain. Mass spectrometric analysis identified heat-shock protein Ssa1 as a Dcp1-interacting protein. Interaction of Dcp1 with Ssa1 was enhanced in yeast with the Vps16 mutation, and the decapping activity of Dcp1 was likely regulated by Ssa1.

▼ Molecular Genetics
Autosomal Dominant Dystonia 30

In 19 patients from 14 unrelated families of European descent with dystonia-30 (DYT30; 619291), Steel et al. (2020) identified heterozygous loss-of-function mutations in the VPS16 gene (see, e.g., 608550.0001-608550.0004). The mutations, which were found by exome sequencing, were absent from the gnomAD database, except for 1 (R635X), which was found once (1 of 248,918 alleles). There were 4 frameshift, 3 nonsense, and 3 splice site mutations; 1 patient had a de novo microdeletion encompassing the VPS16 gene. Four mutations were inherited from a symptomatic parent, and 4 were inherited from an asymptomatic parent, consistent with incomplete penetrance. The inheritance in the remaining patients was unknown. Functional studies of the variants were not performed, but all were predicted to result in haploinsufficiency. Electron microscopic studies of fibroblasts derived from 2 unrelated patients showed increased clusters of vacuoles, some containing particulate or laminated inclusions, suggesting lysosomal dysfunction.

In a 42-year-old German man with DYT30, Pott et al. (2021) identified a heterozygous frameshift mutation in the VPS16 gene (608550.0005). The mutation was found by direct Sanger sequencing; functional studies of the variant were not performed.

Autosomal Recessive Dystonia 30

In 5 members of a multigenerational consanguineous Chinese family with autosomal recessive inheritance of dystonia-30 (DYT30; see 619291), Cai et al. (2016) identified a homozygous missense mutation in the VPS16 gene (N52K; 608550.0006). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies of patient cells were not performed, but generation of mice carrying the N52K mutation using CRISPR-Cas9 technology showed that the mutation caused progressively impaired motor function compared to controls. There was also a decrease in mutant VPS16 protein levels in blood from mutant mice.

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 DYSTONIA 30
VPS16, ARG187TER
In 2 unrelated men (patients 4 and 10) with dystonia-30 (DYT30; 619291), Steel et al. (2020) identified a heterozygous c.559C-T transition (c.559C-T, NM_022575.3) in the VPS16 gene, resulting in an arg187-to-ter (R187X) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. One patient inherited the variant from an unaffected parent; the transmission in the other patient was unknown. Functional studies of the variant were not performed, but it was predicted to result in a loss of function and haploinsufficiency.

.0002 DYSTONIA 30
VPS16, 2-BP DUP, NT1094
In a mother and son (family 7) with dystonia-30 (DYT30; 619291), Steel et al. (2020) identified a heterozygous 2-bp duplication (c.1094_1095dup, NM_022575.3) in the VPS16 gene, resulting in a frameshift and premature termination (Tyr366SerfsTer12). The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but it was predicted to result in a loss of function and haploinsufficiency.

.0003 DYSTONIA 30
VPS16, TYR455TER
In 2 affected members of a family (family 3) with dystonia-30 (DYT30; 619291), Steel et al. (2020) identified a heterozygous c.1335T-G transversion (c.1335T-G, NM_022575.3) in the VPS16 gene, resulting in a tyr455-to-ter (Y455X) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but it was predicted to result in a loss of function and haploinsufficiency.

.0004 DYSTONIA 30
VPS16, IVSDS, T-C, +2
In a 69-year-old woman (patient 8) with dystonia-30 (DYT30; 619291), Steel et al. (2020) identified a heterozygous T-to-C intronic transition (c.1367+2T-C, NM_022575.3) in the VPS16 gene, predicted to result in a splicing defect. She inherited the variant from an affected parent. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but it was predicted to result in a loss of function and haploinsufficiency. Patient fibroblasts showed abnormal vacuoles, suggesting lysosomal dysfunction.

.0005 DYSTONIA 30
VPS16, DEL/INS, NT244
In a 42-year-old German man with dystonia-30 (DYT30; 619291), Pott et al. (2021) identified a heterozygous frameshift mutation in the VPS16 gene (c.244_259delinsGAGAGC), predicted to result in premature termination (Lys82GlufsTer124). The mutation was found by direct Sanger sequencing; functional studies of the variant were not performed.

.0006 DYSTONIA 30, AUTOSOMAL RECESSIVE
VPS16, ASN52LYS
In 5 members of a multigenerational consanguineous Chinese family with autosomal recessive inheritance of dystonia-30 (DYT30; see 619291), Cai et al. (2016) identified a homozygous c.156C-A transversion (c.156C-A, NM_022575.3) in the VPS16 gene, resulting in an asn52-to-lys (N52K) substitution at a highly conserved residue in the beta-propeller domain. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant had a low frequency in the ExAC database (0.0029) among East Asians, with no homozygotes. Studies of patient cells were not performed, but generation of mice carrying the N52K mutation using CRISPR-Cas9 technology showed that the mutation caused progressively impaired motor function compared to controls. There was also a decrease in mutant VPS16 protein levels in blood from mutant mice.

Tags: 20p13