Alternative titles; symbols
HGNC Approved Gene Symbol: VPS13D
Cytogenetic location: 1p36.22-p36.21 Genomic coordinates (GRCh38) : 1:12,230,030-12,512,047 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.22-p36.21 | Spinocerebellar ataxia, autosomal recessive 4 | 607317 | Autosomal recessive | 3 |
The VPS13D gene encodes a ubiquitously expressed protein that plays an important role in mitochondrial size, autophagy, and clearance (summary by Gauthier et al., 2018).
By searching databases for sequences similar to VPS13A (605978), followed by RT-PCR of lymphoid cell line and brain RNA, Velayos-Baeza et al. (2004) cloned VPS13D. They identified 2 main splice variants, variant 1A and variant 2A, based on the presence or absence of exon 40, respectively, and they identified 4 different 3-prime end splice variants in the databases. Variant 1A encodes a deduced 4,388-amino acid protein, and variant 2A encodes a deduced 4,363-amino acid protein. VPS13D shares significant similarity with yeast Vps13 and other human VPS13 proteins, mostly in the N and C termini. Northern blot analysis detected VPS13D expression in all tissues tested. Variant 2A predominated in all tissues except brain and testis, in which variant 1A predominated.
Anding et al. (2018) reported that human and Drosophila VPS13D share 33% amino acid identity. VPS13D contains a ubiquitin-binding UBA domain that is conserved from fly to human. Vps13d localized to lysosomes in Drosophila intestinal cells.
Anding et al. (2018) found that Vps13D was an essential gene in Drosophila that was required for cell size reduction in midgut. Knockdown of Vps13d in larvae revealed that Vps13d acted specifically in developmental autophagy in midgut. Knockdown assays in Drosophila intestinal cells showed that Vps13d functioned downstream of Atg1 (see ULK1, 603168) to mediate a change in ubiquitin associated with control of both mitochondrial morphology and autophagy. Further analysis showed that Vps13d knockdown resulted in a failure of mitochondrial clearance and enlarged mitochondria in Drosophila. Knockdown of human VPS13D in HeLa cells confirmed the phenotype observed in Drosophila. In vitro binding assays demonstrated that the Drosophila Vps13d UBA domain bound to lsy63 tetra-ubiquitin chains. Homozygous in-frame deletion of the Vps13d UBA domain in Drosophila drastically decreased survival rate, and midgut cells possessed enlarged mitochondria and larger cell size compared with controls, indicating that the UBA domain is required for mitochondrial clearance. Similarly, deletion of the human VPS13D UBA domain in HeLa cells resulted in significant mitochondrial morphology defects. The Vps13d mutant phenotype was similar to that of Drp1 (DNM1L; 603850) mutant Drosophila, and investigation of VPS3D mutant HeLa cells suggested that VPS13D may influence DRP1 recruitment to mitochondria. Detailed analysis of Vps13d mutant Drosophila cells revealed that Vps13d was involved in mitochondrial fission and clearance of mitochondria by functioning downstream of Drp1 and upstream of induction of autophagy.
Velayos-Baeza et al. (2004) determined that the VPS13D gene contains 70 exons and spans 280 kb. The translation start codon is in exon 2.
By genomic sequence analysis, Velayos-Baeza et al. (2004) mapped the VPS13D gene to chromosome 1p36. They mapped the mouse Vps13d gene to chromosome 4E1.
In affected members of 2 unrelated families (UM1 and LUB1) with autosomal recessive spinocerebellar ataxia-4 (SCAR4; 607317), Seong et al. (2018) identified compound heterozygous mutations in the VPS13D gene (608877.0001-608877.0004). The mutations in the first family were found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing; this family had previously been reported by Swartz et al. (2002). Mutations in the second family were also found by whole-exome sequencing. International collaboration studies sharing whole-exome data identified 5 additional patients with sporadic occurrence of the disorder who had biallelic mutations in the VPS13D gene. All mutations were confirmed by Sanger sequencing. All but 2 patients were compound heterozygous for a missense and nonsense or splice site mutation. Two patients with a more severe disorder had a combination of a nonsense or frameshift and a splice site mutation.
In 7 patients from 5 unrelated families of various ethnic descent with SCAR4, Gauthier et al. (2018) identified homozygous or compound heterozygous mutations in the VPS13D gene (see, e.g., 608877.0005-608877.0007). The families were collected using the GeneMatcher collaborative project. All mutations were found by exome sequencing and confirmed by Sanger sequencing to segregate with the disorder in the families. Affected members of 3 families were compound heterozygous for a loss-of-function and a missense mutation, whereas affected members of 2 families were homozygous or compound heterozygous for 2 missense mutations. Functional studies of the variants and studies of patient cells were not performed, but muscle biopsy of 1 patient showed mitochondrial abnormalities. Gauthier et al. (2018) postulated a loss-of-function pathogenetic mechanism.
Seong et al. (2018) noted that complete knockdown of the Vps13d homolog in Drosophila and mouse is embryonic lethal. Vps13d-null flies had abnormal mitochondrial morphology. Specific knockdown of the gene in motoneurons resulted in enlarged spherical mitochondria with loss of complexity of the mitochondrial network within neurons as well as impairment of the distribution of mitochondria in the peripheral axons of segmental nerves and neuromuscular junction synapses. The authors noted that these findings could represent defects in mitochondrial fission and fusion.
In affected members of a family (UM1) with autosomal recessive spinocerebellar ataxia-4 (SCAR4; 607317), originally been reported by Swartz et al. (2002), Seong et al. (2018) identified compound heterozygous mutations in the VPS13D gene: a c.3569G-A transition (c.3569G-A, NM_015378), resulting in a gly1190-to-asp (G1190D) substitution at a conserved residue and a c.3316C-T transition, resulting in a gln1106-to-ter (Q1106X; 608877.0002) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the gnomAD database. Analysis of patient cells indicated that the nonsense mutation resulted in nonsense-mediated mRNA decay. Patient fibroblasts showed abnormal mitochondrial morphology, with high amounts of perinuclear spherical or donut-shaped objects and decreased mitochondrial branching compared to controls.
For discussion of the c.3316C-T transition (c.3316C-T, NM_015378) in the VPS13D gene, resulting in a gln1106-to-ter (Q1106X) substitution, that was found in compound heterozygous state in affected members of a family with autosomal recessive spinocerebellar ataxia-4 (SCAR4; 607317) by Seong et al. (2018), see 608877.0001.
In 2 German sisters (family LUB1) with autosomal recessive spinocerebellar ataxia-4 (SCAR4; 607317), Seong et al. (2018) identified compound heterozygous mutations in the VPS13D gene: a c.12629C-T transition (c.12629C-T, NM_015378), resulting in an ala4210-to-val (A4210V) substitution at a conserved residue, and a c.5409C-A transversion, resulting in a tyr1803-to-ter (Y1803X) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The A4210V variant was found at a low frequency (0.00004039) in the gnomAD database; the Y1803X variant was not found in the gnomAD database. Analysis of patient cells indicated that the nonsense mutation resulted in nonsense-mediated mRNA decay. Patient fibroblasts showed decreased mitochondrial branching and reduced ATP production compared to controls.
For discussion of the c.5409C-A transversion (c.5409C-A, NM_015378) in the VPS13D gene, resulting in a tyr1803-to-ter (Y1803X) substitution, that was found in compound heterozygous state in affected members of a family with autosomal recessive spinocerebellar ataxia-4 (SCAR4; 607317) by Seong et al. (2018), see 608877.0003.
In 2 French Canadian brothers (family 1) with autosomal recessive spinocerebellar ataxia-4 (SCAR4; 607317), Gauthier et al. (2018) identified compound heterozygous mutations in the VPS13D gene: a 1-bp deletion (c.7332_7333del, NM_015378.3), predicted to result in a frameshift and premature termination (Val2445GlufsTer16), and a c.10562A-G transition, resulting in an asn3521-to-ser (N3521S; 608877.0006) substitution at a highly conserved residue in the SHR-binding domain. Functional studies of the variants were not performed, but muscle biopsy of 1 of the patients showed subsarcolemmal mitochondrial aggregates and mild lipidosis, suggesting mitochondrial dysfunction.
For discussion of the c.10562A-G transition (c.10562A-G, NM_015378.3) in the VPS13D gene, resulting in an asn3521-to-ser (N3521S) substitution, that was found in compound heterozygous state in affected members of a family with autosomal recessive spinocerebellar ataxia-4 (SCAR4; 607317) by Gauthier et al. (2018), see 608877.0005.
In a 9-year-old girl, born of consanguineous Egyptian parents (family 2), with autosomal recessive spinocerebellar ataxia-4 (SCAR4; 607317), Gauthier et al. (2018) identified a homozygous c.12683G-A transition (c.12683G-A, NM_015378.3) in the VPS13D gene, resulting in an arg4228-to-gln (R4228Q) substitution at a highly conserved residue in the C terminal. The mutation, which was 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.
Anding, A. L., Wang, C., Chang, T.-K., Sliter, D. A., Powers, C. M., Hofmann, K., Youle, R. J., Baehrecke, E. H. Vps13D encodes a ubiquitin-binding protein that is required for the regulation of mitochondrial size and clearance. Curr. Biol. 28: 287-295, 2018. [PubMed: 29307555] [Full Text: https://doi.org/10.1016/j.cub.2017.11.064]
Gauthier, J., Meijer, I. A. Lessel, D., Mencacci, N. E., Krainc, D., Hempel, M., Tsiakas, K., Prokisch, H., Rossignol, E., Helm, M. H., Rodan, L. H., Karamchandani, J., and 11 others. Recessive mutations in VPS13D cause childhood onset movement disorders. Ann. Neurol. 83: 1089-1095, 2018. [PubMed: 29518281] [Full Text: https://doi.org/10.1002/ana.25204]
Seong, E., Insolera, R., Dulovic, M., Kamsteeg, E.-J., Trinh, J., Bruggermann, N., Sandford, E., Li, S., Ozel, A. B., Li, J. Z., Jewett, T., Kievit, A. J. A., Munchau, A., Shakkottai, V., Klein, C., Collins, C. A., Lohmann, K., van de Warrenburg, B. P., Burmeister, M. Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects. Ann. Neurol. 83: 1075-1088, 2018. [PubMed: 29604224] [Full Text: https://doi.org/10.1002/ana.25220]
Swartz, B. E., Burmeister, M., Somers, J. T., Rottach, K. G., Bespalova, I. N., Leigh, R. J. A form of inherited cerebellar ataxia with saccadic intrusions, increased saccadic speed, sensory neuropathy, and myoclonus. Ann. N.Y. Acad. Sci. 956: 441-444, 2002. [PubMed: 11960835] [Full Text: https://doi.org/10.1111/j.1749-6632.2002.tb02850.x]
Velayos-Baeza, A., Vettori, A., Copley, R. R., Dobson-Stone, C., Monaco, A. P. Analysis of the human VPS13 gene family. Genomics 84: 536-549, 2004. [PubMed: 15498460] [Full Text: https://doi.org/10.1016/j.ygeno.2004.04.012]