HGNC Approved Gene Symbol: ARSK
Cytogenetic location: 5q15 Genomic coordinates (GRCh38) : 5:95,555,101-95,605,102 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q15 | Mucopolysaccharidosis, type X | 619698 | Autosomal recessive | 3 |
Sulfatases such as arylsulfatase K (ARSK) hydrolyze sulfate esters from sulfated steroids, carbohydrates, proteoglycans, and glycolipids. They are involved in hormone biosynthesis, modulation of cell signaling, and degradation of macromolecules (summary by Sardiello et al., 2005).
By searching databases for novel sulfatase genes, Sardiello et al. (2005) and Obaya (2006) identified ARSK. They determined that all human sulfatases, including ARSK, have 9 regions of strong evolutionary conservation, most of which contain residues involved in the sulfatase hydrolysis reaction.
Obaya (2006) determined that the deduced 536-amino acid ARSK protein has a predicted molecular mass of about 61.5 kD. Western blot analysis of HeLa cells expressing epitope-tagged ARSK detected the protein only in the particulate fraction, suggesting that ARSK associates with cellular organelles or membrane structures.
By RT-PCR analysis, Wiegmann et al. (2013) detected ARSK mRNA expression in all tissues tested, suggesting a common and widespread substrate.
Wiegmann et al. (2013) showed that, when expressed in human cells, ARSK occurs as a 68-kD protein with arylsulfatase activity. Optimum activity occurred at about pH 4.6. The protein colocalized with LAMP1 (153300), indicating that it functions within lysosomes.
Obaya (2006) determined that the ARSK gene contains 8 exons and spans about 48.3 kb.
Sardiello et al. (2005) and Obaya (2006) stated that the ARSK gene maps to chromosome 5q15. Obaya (2006) determined that the mouse Arsk gene maps to chromosome 13.
In 2 sib pairs with mucopolysaccharidosis type X (MPS10; 619698) from consanguineous families of Turkish and Indian descent, respectively, Verheyen et al. (2022) identified homozygous mutations in the ARSK gene (R84C, 610011.0001 and L187X, 610011.0002). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the families. Functional studies in HT1080 cells showed that the R84C mutation resulted in a protein with reduced enzymatic activity and the L187X mutation resulted in absence of protein expression. All 4 patients had coarse facial features, disproportionate short-trunk short stature, and genu valgus; 2 of 2 patients tested had increased dermatan sulfate in the urine.
In 2 Turkish sibs (family 1), born to consanguineous parents, with mucopolysaccharidosis type X (MPS10; 619698), Verheyen et al. (2022) identified homozygosity for a c.250C-T transition (c.250C-T, NM_198150.2) in the ARSK gene, resulting in an arg84-to-cys (R84C) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygosity in the parents. The mutation affects a highly conserved sulfatase signature and is important for oxidation of a cysteine into a formylglycine residue. The mutation was present in the gnomAD database at an allele frequency of 0.002129% with no homozygotes reported. Expression studies in HT1080 cells showed that the R85C mutation resulted in reduced ARSK activity.
In 2 Indian sibs (family 2), born to consanguineous parents, with mucopolysaccharidosis type X (MPS10; 619698), Verheyen et al. (2022) identified homozygosity for a c.560T-A transversion (c.560T-A, NM_198150.2) in the ARSK gene, resulting in a leu187-to-ter (L187X) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was present in the gnomAD database at an allele frequency of 0.0003980% with no homozygotes reported. Expression studies in HT1080 cells showed that the L187X mutation resulted in absent protein expression, consistent with mRNA nonsense-mediated decay or instability of a truncated protein.
Obaya, A. J. Molecular cloning and initial characterization of three novel human sulfatases. Gene 372: 110-117, 2006. [PubMed: 16500042] [Full Text: https://doi.org/10.1016/j.gene.2005.12.023]
Sardiello, M., Annunziata, I., Roma, G., Ballabio, A. Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship. Hum. Molec. Genet. 14: 3203-3217, 2005. [PubMed: 16174644] [Full Text: https://doi.org/10.1093/hmg/ddi351]
Verheyen, S., Blatterer, J., Speicher, M. R., Bhavani, G. S., Boons, G.-J., Ilse, M.-B., Andrae, D., Spross, J., Vaz, F. M., Kircher, S. G., Posch-Pertl, L., Baumgartner, D., Lubke, T., Shah, H., Al Kaissi, A., Girisha, K., Plecko, B. Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency. J. Med. Genet. 59: 957-964, 2022. [PubMed: 34916232] [Full Text: https://doi.org/10.1136/jmedgenet-2021-108061]
Wiegmann, E. M., Westendorf, E., Kalus, I., Pringle, T. H., Lubke, T., Dierks, T. Arylsulfatase K, a novel lysosomal sulfatase. J. Biol. Chem. 288: 30019-30028, 2013. [PubMed: 23986440] [Full Text: https://doi.org/10.1074/jbc.M113.499541]