Alternative titles; symbols
HGNC Approved Gene Symbol: GNS
SNOMEDCT: 15892005; ICD10CM: E76.22;
Cytogenetic location: 12q14.3 Genomic coordinates (GRCh38) : 12:64,713,449-64,759,406 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q14.3 | Mucopolysaccharidosis type IIID | 252940 | Autosomal recessive | 3 |
N-acetylglucosamine-6-sulfatase (GNS; EC 3.1.6.14) hydrolyzes heparan sulfate and keratan sulfate (Freeman et al., 1987).
Freeman et al. (1987) reported purification and characterization of GNS. They identified 4 forms of the enzyme in liver, which were postulated to be due to differences in the state of processing of a large subunit.
Using sequences obtained by direct N-terminal amino acid sequencing of G6S isoforms, Robertson et al. (1988) designed oligonucleotide probes to screen a liver cDNA library. The longest clone obtained encoded a deduced 375-amino acid protein representing form A of G6S. They also identified a clone that represents the 331-amino acid form B of G6S. Robertson et al. (1988) determined that the N-terminal amino acid sequence of the 78-kD form A species and the 32-kD form B species are identical, indicating that the 78-kD form A polypeptide is processed by internal peptidase cleavage to a 32-kD N-terminal species and a 48-kD C-terminal species. Full-length G6S contains several N-glycosylation sites and a hydrophilic region, rich in basic amino acids, that may represent the proteolytic cleavage site.
The catalytic properties of GNS were studied by Freeman and Hopwood (1987).
Dhoot et al. (2001) reported the identification and characterization of QSulf1, an avian ortholog of GNS. QSulf1 expression is induced by Sonic hedgehog in myogenic somite progenitors in quail embryos and is required for the activation of MyoD (159970), a Wnt (see 164820)-induced regulator of muscle specification. QSulf1 is localized on the cell surface and regulates heparan-dependent Wnt signaling in C2C12 myogenic progenitor cells through a mechanism that requires its catalytic activity, providing evidence that QSulf1 regulates Wnt signaling through desulfation of cell surface heparan sulfate proteoglycans.
Robertson et al. (1988) assigned the glucosamine-6-sulfatase gene, which they symbolized G6S, to chromosome 12q14 by in situ hybridization of a tritium-labeled G6S cDNA probe. The localization was confirmed by using the cDNA clone in 7 analyses of DNA from human/mouse hybrid cell lines.
Mok et al. (2003) amplified and sequenced the promoter and 14 exons of the GNS gene from a patient with mucopolysaccharidosis type IIID (MPS3D; 252940) and identified a homozygous nonsense mutation in exon 9, predicted to result in premature termination at codon 355 (607664.0001). They also identified 2 common synonymous coding SNPs and genotyped these in samples from 4 ethnic groups.
Independently, Beesley et al. (2003) identified a 1-bp deletion in the GNS gene (607664.0002) in a patient with Sanfilippo disease (mucopolysaccharidosis) type D.
Elcioglu et al. (2009) reported a 10-year-old Turkish boy with Sanfilippo syndrome type D, in whom they identified homozygosity for a 1-bp insertion in the GNS gene (607664.0005). The authors stated that this was the twenty-first patient and the eighth mutation reported for the disease.
In the fibroblast cell line of the 7-year-old East Indian boy with mucopolysaccharidosis type IIID (MPS3D; 252940) described by Kresse et al. (1980), Mok et al. (2003) identified a homozygous 1063C-T transition in exon 9 of the GNS gene, predicting a premature termination of translation at codon 355 (R355X).
In a patient with mucopolysaccharidosis type IIID (252940), Beesley et al. (2003) identified homozygosity for a 1-bp deletion, 1169delA, in the GNS gene. The mutation was predicted to cause a frameshift and premature termination of the protein. The patient was the offspring of first-cousin parents from Pakistan. He presented at 3 years of age, at which time he was very 'lively' and examination was difficult as he was very fractious. He had a hirsute facies and his facial features were coarse. He had a large head with frontal bossing, a low nasal bridge, and a tendency to hypertelorism. His tongue and hands were large. There was no hepatosplenomegaly or audible murmurs. A skeletal survey was consistent with a mucopolysaccharidosis.
In 2 Italian Canadian brothers with mucopolysaccharidosis type IIID (252940), originally reported by Kaplan and Wolfe (1987), Jansen et al. (2007) identified a homozygous 1168C-T transition in exon 10 of the GNS gene, resulting in a gln390-to-ter (Q390X) substitution. Each unaffected parent was heterozygous for the mutation.
In a 15-year-old Turkish English girl with mucopolysaccharidosis type IIID (252940), Jansen et al. (2007) identified a homozygous 5-bp insertion (1138insGTCCT) in exon 10 of the GNS gene, resulting in a frameshift and premature termination of the protein at residue 389. She was severely retarded and fully dependent on assistance for all activities of daily living.
In a 10-year-old Turkish boy with mucopolysaccharidosis type IIID (252940), Elcioglu et al. (2009) identified homozygosity for a 1-bp insertion (1226insG) in exon 11 of the GNS gene, predicted to cause a frameshift and premature termination with loss of the C terminus. The boy's parents were heterozygous for the mutation, which was not found in 100 controls.
Beesley, C. E., Burke, D., Jackson, M., Vellodi, A., Winchester, B. G., Young, E. P. Sanfilippo syndrome type D: identification of the first mutation in the N-acetylglucosamine-6-sulphatase gene. J. Med. Genet. 40: 192-194, 2003. [PubMed: 12624138] [Full Text: https://doi.org/10.1136/jmg.40.3.192]
Dhoot, G. K., Gustafsson, M. K., Ai, X., Sun, W., Standiford, D. M., Emerson, C. P., Jr. Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase. Science 293: 1663-1666, 2001. [PubMed: 11533491] [Full Text: https://doi.org/10.1126/science.293.5535.1663]
Elcioglu, N. H., Pawlik, P., Colak, B., Beck, M., Wollnik, B. A novel loss-of-function mutation in the GNS gene causes Sanfilippo syndrome type D. Genet. Counsel. 20: 133-139, 2009. [PubMed: 19650410]
Freeman, C., Clements, P. R., Hopwood, J. J. Human liver N-acetylglucosamine-6-sulphate sulphatase: purification and characterization. Biochem. J. 246: 347-354, 1987. [PubMed: 3689314] [Full Text: https://doi.org/10.1042/bj2460347]
Freeman, C., Hopwood, J. J. Human liver N-acetylglucosamine-6-sulphate sulphatase: catalytic properties. Biochem. J. 246: 355-365, 1987. [PubMed: 3689315] [Full Text: https://doi.org/10.1042/bj2460355]
Jansen, A. C. M., Cao, H., Kaplan, P., Silver, K., Leonard, G., De Meileir, L., Lissens, W., Liebaers, I., Veilleux, M., Andermann, F., Hegele, R. A., Andermann, E. Sanfilippo syndrome type D: natural history and identification of 3 novel mutations in the GNS gene. Arch. Neurol. 64: 1629-1634, 2007. [PubMed: 17998446] [Full Text: https://doi.org/10.1001/archneur.64.11.1629]
Kaplan, P., Wolfe, L. S. Sanfilippo syndrome type D. J. Pediat. 110: 267-271, 1987. [PubMed: 3100754] [Full Text: https://doi.org/10.1016/s0022-3476(87)80171-3]
Kresse, H., Paschke, E., von Figura, K., Gilberg, W., Fuchs, W. Sanfilippo disease type D: deficiency of N-acetylglucosamine-6-sulfate sulfatase required for heparan sulfate degradation. Proc. Nat. Acad. Sci. 77: 6822-6826, 1980. [PubMed: 6450420] [Full Text: https://doi.org/10.1073/pnas.77.11.6822]
Mok, A., Cao, H., Hegele, R. A. Genomic basis of mucopolysaccharidosis type IIID (MIM 252940) revealed by sequencing of GNS encoding N-acetylglucosamine-6-sulfatase. Genomics 81: 1-5, 2003. [PubMed: 12573255] [Full Text: https://doi.org/10.1016/s0888-7543(02)00014-9]
Robertson, D. A., Callen, D. F., Baker, E. G., Morris, C. P., Hopwood, J. J. Chromosomal localization of the gene for human glucosamine-6-sulphatase to 12q14. Hum. Genet. 79: 175-178, 1988. [PubMed: 3391615] [Full Text: https://doi.org/10.1007/BF00280560]
Robertson, D. A., Freeman, C., Nelson, P. V., Morris, C. P., Hopwood, J. J. Human glucosamine-6-sulfatase cDNA reveals homology with steroid sulfatase. Biochem. Biophys. Res. Commun. 157: 218-224, 1988. [PubMed: 3196333] [Full Text: https://doi.org/10.1016/s0006-291x(88)80035-4]