Alternative titles; symbols
HGNC Approved Gene Symbol: ATP6V0A2
SNOMEDCT: 238875009, 784381008;
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38) : 12:123,712,353-123,761,755 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.31 | Cutis laxa, autosomal recessive, type IIA | 219200 | Autosomal recessive | 3 |
| Wrinkly skin syndrome | 278250 | Autosomal recessive | 3 |
The multisubunit vacuolar-type proton pump (H(+)-ATPase or V-ATPase) is essential for acidification of diverse cellular components, including endosomes, lysosomes, clathrin-coated vesicles, secretory vesicles, and chromaffin granules, and it is found at high density in the plasma membrane of certain specialized cells. H(+)-ATPases are composed of a peripheral V(1) domain and an integral membrane V(0) domain; ATP6V0A2 is a component of the V(0) domain (Smith et al., 2003).
By screening for secreted immune regulatory proteins, Lee et al. (1990) cloned Atp6v0a2, which they called J6B7, from a mouse helper T cell hybridoma cDNA library. The deduced protein has a hydrophobic N terminus and 3 potential N-glycosylation sites, and it has a calculated molecular mass of 98.0 kD. Northern blot analysis detected abundant expression in the T cell hybridoma cells and in mouse thymus, but not in thymoma, spleen, or liver.
Using flow cytometry and immunofluorescence microscopy, Ntrivalas et al. (2007) showed that A2V-ATPase was expressed at the cell membrane and intracellularly in the JEG-3 human choriocarcinoma cell line.
Lee et al. (1990) found that mouse Atp6v0a2 showed significant suppression of a mixed lymphocyte reaction in a dose-dependent manner.
Ntrivalas et al. (2007) stated that upon cell stimulation, A2V- ATPase migrates to the cell membrane as a 50-kD molecule and the remaining 20-kD N-terminal domain is secreted into the extracellular environment. The authors showed that secretion of IL1B (147720) was increased and expression of type I and II interleukin receptors IL1R1 (147810) and IL1R2 (147811) were significantly decreased by the A2V-ATPase N-terminal domain in human peripheral blood mononuclear cells cocultured with JEG-3 cells.
By homozygosity mapping in 15 consanguineous families, Kornak et al. (2008) identified a critical region for autosomal recessive cutis laxa (219200) on chromosome 12q24 containing the ATP6V0A2 gene.
Manifestations in cases of autosomal recessive cutis laxa (ARCL) type II (Debre type) (ARCL2A; 219200) and wrinkly skin syndrome (WSS; 278250) include, in addition to excessive congenital skin wrinkling, large fontanel with delayed closure, typical facial appearance with downslanting palpebral fissures, a general connective tissue weakness, and varying degrees of growth and developmental delay and neurologic abnormalities. Some affected individuals develop seizures and mental deterioration later in life, whereas the skin phenotype tends to become milder with age. Because an association of a cutis laxa phenotype with a congenital disorder of glycosylation had been described and wrinkly skin observed in an individual with a defect in the conserved oligomeric Golgi (COG) complex involved in Golgi membrane trafficking, Kornak et al. (2008) investigated glycosylation of serum proteins isolated from individuals with ARCL type II. All affected individuals showed a CDG type II (CDG II) pattern, which corresponds to a defect of N-glycosylation at the level of processing in the Golgi apparatus. By homozygosity mapping in 15 consanguineous families, Kornak et al. (2008) identified a homozygous region on chromosome 12q24 with a maximum lod score of 3.2 in 12 families. The products of 9 of the genes in the critical linkage region were part of the Golgi proteome. In 12 families with diagnoses of either autosomal recessive cutis laxa type II or wrinkly skin syndrome, Kornak et al. (2008) identified 10 different loss-of-function mutations in the ATP6V0A2 gene (see, e.g., 611716.0001-611716.0003). Four were splice site mutations, 3 were nonsense, and 3 frameshift; 5 mutations led to a premature stop in the cytoplasmic N terminus, which is thought to mediate interaction with other ATPase subunits, and the other mutations led to truncations in transmembrane segments III, VI, and VIII. The mutations resulted in abnormal glycosylation of serum proteins (CDG II) and caused an impairment of Golgi trafficking in fibroblasts from affected individuals. The results indicated that the alpha-2 subunit of the proton pump has an important role in the Golgi function.
Hucthagowder et al. (2009) determined the molecular defects in ATP6V0A2 in a cohort of 17 patients with autosomal recessive cutis laxa. Considerable allelic and phenotypic heterogeneity was observed. Abnormal N- and/or mucin type O-glycosylation was observed in all patients tested.
In 13 patients with ARCL2, Fischer et al. (2012) identified 17 ATP6V0A2 mutations: 1 mutation of the start codon, 3 missense mutations, 3 nonsense mutations, 3 splice site mutations, 3 in-frame deletions, and 4 frameshift mutations; 14 of the mutations were novel. All mutations but 1 were found in homozygous or compound heterozygous state. A heterozygous splice site mutation (117+1delG) was detected at the genomic as well as the cDNA level in a 40-year-old patient (patient 2), but a pronounced nonsense-mediated decay of the ATP6V0A2 mRNA in fibroblasts corroborated an ATP6V0A2-related ARCL2. Fischer et al. (2012) suggested that the second mutation most probably resided in noncoding regions not included in the mutation screening.
Hucthagowder et al. (2009) showed that premature stop codon mutations (see 611716.0001) led to decreased ATP6V0A2 mRNA levels by destabilizing the mutant mRNA via the nonsense-mediated decay pathway. Loss of ATP6V0A2 either by siRNA knockdown or in ARCL2 cells resulted in distended Golgi cisternae, accumulation of abnormal lysosomes and multivesicular bodies. Immunostaining of ARCL2 cells showed the accumulation of tropoelastin (ELN; 130160) in the Golgi and in large, abnormal intracellular and extracellular aggregates. Pulse-chase studies confirmed impaired secretion and increased intracellular retention of ELN, and insoluble elastin assays showed significantly reduced extracellular deposition of mature elastin. Fibrillin-1 (FBN1; 134797) microfibril assembly and secreted lysyl oxidase (LOX; 153455) activity were normal in ARCL2 cells. TUNEL staining demonstrated increased rates of apoptosis in ARCL2 cell cultures. Hucthagowder et al. (2009) concluded that loss-of-function mutations in ATP6V0A2 lead to ELN aggregation in the Golgi, impaired clearance of ELN aggregates, and increased apoptosis of elastogenic cells.
By immunostaining with an antibody against ATP6V0A2, Fischer et al. (2012) demonstrated localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in the dermal fibroblasts of patients with ARCL2A. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB (607983) and PYCR1 (179035). Furthermore, by detection of P-Smad2, Fischer et al. (2012) demonstrated that fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-beta signaling and increased TGFB1 (190180) levels in the supernatant.
In a Hispanic individual with type IIA autosomal recessive cutis laxa with a congenital disorder of glycosylation type II (CDG II) pattern (ARCL2A; 219200), Kornak et al. (2008) identified a nonsense mutation in the ATP6V0A2 gene: 2293C-T, gln765 to stop (Q765X). The mutation occurred in the eighth transmembrane domain of the protein.
In 2 Turkish individuals with autosomal recessive cutis laxa type IIA with a congenital disorder of glycosylation type II (CDG II) pattern (ARCL2A; 219200), Kornak et al. (2008) identified a nonsense mutation in the ATP6V0A2 gene: 187C-T, arg63 to stop (R63X). The mutation occurred in the cytoplasmic N-terminal domain. One of the patients had been reported by Morava et al. (2005).
In 3 families from Oman, Kornak et al. (2008) identified a nonsense mutation in the ATP6V0A2 gene in association with wrinkly skin syndrome (WSS; 278250): 294+1G-A, resulting in frameshift at val66 and premature protein termination (Val66fsTer107). Typical facial dysmorphism and depression in the frontal calvaria due to a large open fontanel as well as skin wrinkling in neck and abdomen were illustrated in one of the patients.
In an Indian patient with autosomal recessive cutis laxa type IIA (ARCL2A; 219200), Fischer et al. (2012) identified homozygosity for a 7-bp deletion in the ATP6V0A2 gene (2355-2361delTGGCGTC) resulting in a frameshift (Tyr785fsTer800).
In a Turkish patient from a consanguineous family segregating type IIA autosomal recessive cutis laxa type IIA (ARCL2A; 219200), Fischer et al. (2012) identified homozygosity for a 1-bp insertion (100_101insA) in the ATP6V0A2 gene resulting in a frameshift (Val476SfsTer499).
Fischer, B., Dimopoulou, A., Egerer, J., Gardeitchik, T., Kidd, A., Jost, D., Kayserili, H., Alanay, Y., Tantcheva-Poor, I., Mangold, E., Daumer-Haas, C., Phadke, S., and 13 others. Further characterization of ATP6V0A2-related autosomal recessive cutis laxa. Hum. Genet. 131: 1761-1773, 2012. [PubMed: 22773132] [Full Text: https://doi.org/10.1007/s00439-012-1197-8]
Hucthagowder, V., Morava, E., Kornak, U., Lefeber, D. J., Fischer, B., Dimopoulou, A., Aldinger, A., Choi, J., Davis, E. C., Abuelo, D. N., Adamowicz, M., Al-Aama, J., and 14 others. Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival. Hum. Molec. Genet. 18: 2149-2165, 2009. [PubMed: 19321599] [Full Text: https://doi.org/10.1093/hmg/ddp148]
Kornak, U., Reynders, E., Dimopoulou, A., van Reeuwijk, J., Fischer, B., Rajab, A., Budde, B., Nurnberg, P., Foulquier, F., ARCL Debre-type Study Group, Lefeber, D., Urban, Z., and 9 others. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H(+)-ATPase subunit ATP6V0A2. Nature Genet. 40: 32-34, 2008. [PubMed: 18157129] [Full Text: https://doi.org/10.1038/ng.2007.45]
Lee, C., Ghoshal, K., Beaman, K. D. Cloning of a cDNA for a T cell produced molecule with a putative immune regulatory role. Molec. Immun. 27: 1137-1144, 1990. [PubMed: 2247090] [Full Text: https://doi.org/10.1016/0161-5890(90)90102-6]
Morava, E., Wopereis, S., Coucke, P., Gillessen-Kaesbach, G., Voit, T., Smeitink, J., Wevers, R., Grunewald, S. Defective protein glycosylation in patients with cutis laxa syndrome. Europ. J. Hum. Genet. 13: 414-421, 2005. [PubMed: 15657616] [Full Text: https://doi.org/10.1038/sj.ejhg.5201361]
Ntrivalas, E., Gilman-Sachs, A., Kwak-Kim, J., Beaman, K. The N-terminus domain of the a2 isoform of vacuolar ATPase can regulate interleukin-1-beta production from mononuclear cells in co-culture with JEG-3 choriocarcinoma cells. Am. J. Reprod. Immunol. 57: 201-309, 2007. [PubMed: 17295899] [Full Text: https://doi.org/10.1111/j.1600-0897.2006.00463.x]
Smith, A. N., Lovering, R. C., Futai, M., Takeda, J., Brown, D., Karet, F. E. Revised nomenclature for mammalian vacuolar-type H(+)-ATPase subunit genes. Molec. Cell 12: 801-803, 2003. [PubMed: 14580332] [Full Text: https://doi.org/10.1016/s1097-2765(03)00397-6]