Alternative titles; symbols
HGNC Approved Gene Symbol: GALNS
SNOMEDCT: 130197005, 7259005; ICD10CM: E76.210;
Cytogenetic location: 16q24.3 Genomic coordinates (GRCh38) : 16:88,813,734-88,856,947 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.3 | Mucopolysaccharidosis IVA | 253000 | Autosomal recessive | 3 |
The GALNS gene encodes N-acetylgalactosamine-sulfate sulfatase (EC 3.1.6.4), a lysosomal enzyme involved in the catabolism of keratan and chondroitin sulfate.
Gibson et al. (1987) purified and characterized the GALNS enzyme.
Tomatsu et al. (1991) cloned and sequenced a full-length cDNA of human placental N-acetylgalactosamine-6-sulfate sulfatase. The deduced 522-residue protein is composed of a 26-amino acid N-terminal signal peptide and a mature polypeptide of 496 amino acid residues, including 2 potential asparagine-linked glycosylation sites. Expression of the cDNA in transfected deficient fibroblasts resulted in higher production of the sulfatase activity compared to untransfected cells. The amino acid sequence showed a high degree of homology with those of other sulfatases, including human arylsulfatases A (607574), B (611542), and C (300747), glucosamine-6-sulfatase (607664), and iduronate-2-sulfatase (300823).
Nakashima et al. (1994) determined that the human GALNS gene contains 14 exons and spans approximately 50 kb. By deletion analysis, they found the region -98 to -1 upstream of the ATG codon to be a minimal promoter.
Morris et al. (1994) found that the GALNS gene contains 14 exons and spans approximately 40 kb. The potential promoter for GALNS lacks a TATA box but contains GC box consensus sequences, consistent with its role as a housekeeping gene. The GALNS gene contains an Alu repeat in intron 5 and a VNTR-like sequence in intron 6.
Tomatsu et al. (1992) demonstrated that the GALNS gene is located on chromosome 16q24 by fluorescence in situ hybridization. Baker et al. (1993), also using fluorescence in situ hybridization, mapped the gene to 16q24.3. The authors also confirmed the localization to this band by PCR analysis of the somatic cell hybrid panel used for fine mapping of chromosome 16.
In patients with mucopolysaccharidosis type IVA (253000), also known as Morquio syndrome A, Tomatsu et al. (1992) identified 4 different mutations in the GALNS gene (612222.0001-612222.0004).
In 5 unrelated Japanese patients with MPS IVA, Hori et al. (1995) found, in heteroallelic state, 2 separate deletions of nearly 8.0 and 6.0 kb in the GALNS gene. There were Alu repetitive elements near the breakpoints of the 8.0-kb deletion; this deletion had clearly resulted from an Alu-Alu recombination. The 6.0-kb deletion involved illegitimate recombinational events between incomplete short direct repeats of 8 bp at the deletion breakpoints. This was the first documentation of a frequently occurring double deletion in a gene that is not a member of a gene cluster. One of the patients was homozygous for the double deletion, and the others were heterozygous. In the 4 who were heterozygous, Tomatsu et al. (1996) identified novel mutations in the GALNS gene on the other allele: 1 nonsense and 3 missense.
Wang et al. (2010) identified 27 GALNS mutations, including 16 novel mutations, among 24 Chinese patients with MPS IVA. Approximately 63% of the mutations found among the Chinese patients were not observed in other countries, suggesting that a different mutational spectrum may exist in the Chinese population. The most common mutation G340D (612222.0018) was present in 8 (16.7%) of 48 mutant alleles and was found only in 5 patients from central eastern China. Haplotype analysis indicated a founder effect.
Caciotti et al. (2015) studied 37 Italian MPS IVA patients and found that standard sequencing procedures failed to characterize the second disease-causing mutation in 16 percent of patients. Searching for large rearrangements and mRNA defects in this 16% identified splicing defects or large deletions on the other allele in 67% of these. Caciotti et al. (2015) reported 14 novel mutations in GALNS among the 37 patients.
Sukegawa et al. (2000) studied 15 missense mutations and 2 newly engineered active site mutations (C79S, C79T) in the GALNS gene by transient expression analysis. Mutant proteins, except for C79S and C79T, were destabilized and detected as insoluble precursor forms, while the C79S and C79T mutants were of a soluble mature size. Mutations identified in patients with the severe phenotype had no activity, whereas mutations identified in patients with the mild phenotype had a considerable residual activity (1.3-13.3% of wildtype GALNS activity). Sukegawa et al. (2000) also constructed a tertiary structural model of human GALNS from the x-ray crystal structure of homologous sulfatases and investigated 32 missense mutations. The authors proposed 3 different biochemical models for the severe phenotype: (i) destruction of the hydrophobic core or modification of the packing; (ii) removal of a salt bridge to destabilize the entire conformation; (iii) modification of the active site. In contrast, mild mutations were mostly located on the surface of the GALNS protein.
Tomatsu et al. (2003) generated transgenic mice homozygous for a disruption in exon 2 of the Galns gene. These mice had no detectable GALNS enzyme activity, showed increased urinary glycosaminoglycan levels, and accumulated glycosaminoglycans in multiple tissues including liver, kidney, spleen, heart, brain, and bone marrow. At 2 months old, lysosomal storage was present primarily within reticuloendothelial cells. By 12 months old, vacuolar change was observed in glomeruli and heart valves. In the brain, hippocampal and neocortical neurons and meningeal cells had lysosomal storage, and keratan sulfate and chondroitin-6-sulfate were more abundant in corneal epithelial cells of Galns -/- mice. Surprisingly, radiographs revealed no change in the skeletal bones of mice up to 12 months old.
In 2 brothers with a mild form of Morquio syndrome A (253000), Fukuda et al. (1992) and Tomatsu et al. (1992) identified a homozygous 667C-G transversion in the GALNS gene, resulting in an asn204-to-lys (N204K) substitution. Both unaffected parents were heterozygous for the mutation. Transient expression of the mutant allele in GALNS-deficient fibroblasts showed markedly decreased enzyme activity.
In a patient with a severe form of Morquio syndrome A (253000), Tomatsu et al. (1992) identified a homozygous 468T-C transition in the GALNS gene, resulting in an ala138-to-val (A138V) substitution.
In a patient with severe Morquio syndrome A (253000), Tomatsu et al. (1992) identified a 386C-T transition in the GALNS gene, resulting in an arg386-to-cys (R386C) substitution. A PCR method was used for complete cDNA sequencing.
In a study of 20 MPS IVA patients from Latin America, including 16 with a severe phenotype and 4 with an attenuated phenotype, Tomatsu et al. (2004) identified 12 different mutations in the GALNS gene, 9 of which were previously unreported. The R386C mutation accounted for 32.5% of the unrelated mutant alleles. It was identified in all the Latin American populations studied and was associated with a severe form of the disorder. MPS IVA patients had increased urine and plasma keratan sulfate concentrations compared to normal controls. Keratan sulfate concentrations were higher in patients with a severe phenotype than in those with the attenuated form of the disorder.
In a Japanese patient, born of consanguineous parents, with a severe form of Morquio syndrome A (253000), Fukuda et al. (1992) and Tomatsu et al. (1992) identified a homozygous 2-bp deletion in the GALNS gene (1343delCA). Fukuda et al. (1992) referred to the mutation as 1342delCA. This mutation was revealed by TaqI restriction analysis of a cDNA fragment amplified by the polymerase chain reaction.
In Caucasian patients with Morquio syndrome A (253000), Tomatsu et al. (1995) identified a 393A-T transversion in the GALNS gene, resulting in an ile113-to-phe (I113F) substitution. Allele-specific oligonucleotide (ASO) or SSCP analysis indicated that this mutation accounted for 9 (22.5%) of 40 unrelated mutant chromosomes from 23 Caucasian patients, including 6 consanguineous cases. It was not found among 20 Japanese patients. In addition to this common mutation, 10 different point mutations and 2 small deletions were detected.
Among 23 Australian or Irish patients with Morquio syndrome A and various clinical phenotypes, Yamada et al. (1998) found that the I113F mutation was associated with a severe phenotype. The relative frequency of the I113F mutation in Australia corresponded to that observed in Northern Ireland, suggesting that both mutations were probably introduced to Australia by Irish migrants during the 19th century. Haplotype analysis provided additional data that the I113F mutation originated from a common ancestor.
In a patient with severe Morquio disease (253000), Tomatsu et al. (1995) identified compound heterozygosity for 2 mutations in exon 13 of the GALNS gene: a C-to-T transition resulting in a gln473-to-ter (Q473X) substitution, and an A-to-G transition resulting in an asn487-to-ser substitution (N487S; 612222.0007).
See 612222.0006 and Tomatsu et al. (1995).
In 2 Polish sibs with Morquio syndrome (253000), Bunge et al. (1997) identified compound heterozygosity for 2 mutations in the GALNS gene: an arg94-to-gly (R94G) substitution inherited from the father and an arg259-to-gln (R259Q; 612222.0009) substitution inherited from the mother. The sibs were diagnosed at 5 and 6 years of age, respectively. At ages 13 and 14, they were still considered to be mildly affected, with mild thoracolumbar kyphosis, slight prominence of the sternum, hypermobility of ligaments, hip hypoplasia in the boy only, no corneal clouding, and normal height. Their mother, who was homozygous for the R259Q mutation, was found to have greatly reduced enzymatic activity, but only limited manifestations of MPS IVA: short trunk with slight prominence of sternum, and hoarse voice. She had no corneal clouding and was 1.60 m tall.
See 612222.0008 and Bunge et al. (1997).
Tylki-Szymanska et al. (1998) described a 2-generation Morquio A (253000) family with 2 distinct clinical phenotypes. The 2 probands from the second generation showed intermediate signs of the disease, whereas their affected mother, aunt, and 2 uncles had only very mild symptoms. Galactose-6-sulfatase activity in leukocytes and fibroblasts of the affected family members was clearly deficient. Molecular genetic analysis of the GALNS gene showed that 2 different point mutations segregated in the family and correlated well with the clinical phenotype. The probands with intermediate severity of symptoms were compound heterozygous for the R94G mutation (612222.0008), which was inherited from the unaffected father, and for R259Q. The mother and her affected sibs with the unusually mild phenotype were homozygous for the R259Q mutation.
Kato et al. (1997) identified 3 novel missense mutations in 16 of 19 Colombian Morquio syndrome A unrelated alleles (84.2%). A gly301-to-cys (G301C) mutation and a S162F (612222.0011) mutation accounted for 68.4% and 10.5% of mutations, respectively, whereas the third mutation, F69V, (612222.0012), was limited to a single allele. The skewed prevalence of G301C in Colombian patients and haplotype analysis by restriction fragment length polymorphisms in the GALNS gene suggested that G301C originated from a common ancestor. Investigation of a genetic background by means of mtDNA lineages indicated that all of the Colombian patients were probably of Native American descent.
See 612222.0010 and Kato et al. (1997).
See 612222.0010 and Kato et al. (1997).
Studies of patients from the British-Irish population have shown that the I113F (612222.0005) mutation in the GALNS gene is the most common single mutation among Morquio syndrome A patients and produces a severe clinical phenotype. Yamada et al. (1998) studied mutations in the GALNS gene from 23 additional patients (15 from Australia, 8 from Northern Ireland) with various clinical phenotypes (severe, 16 cases; intermediate, 4 cases; mild, 3 cases). They found 2 common mutations that together accounted for 32% of the 44 unrelated alleles in these patients. One was a thr312-to-ser (T312S) substitution, found exclusively in milder patients, and the other was I113F, which produced a severe phenotype. Relatively high residual GALNS activity seen when the T312S mutant cDNA was overexpressed in mutant cells provided an explanation for the mild phenotype in patients with this mutation. The disruption and relative frequency of the I113F and T312S mutations in Australia corresponded to those observed in Northern Ireland and were unique to these 2 populations, suggesting that both mutations were probably introduced to Australia by Irish migrants during the 19th century. Haplotype analysis provided additional data that the I113F mutation originated from a common ancestor. The other 9 novel mutations identified in these 23 patients were each limited to a single family.
Montano et al. (2003) described the clinical phenotype of 5 patients from 3 unrelated Finnish families with Morquio A disease and characterized the disease-causing mutations in GALNS. In all 3 families the affected individuals were compound heterozygous for an asp60-to-asn (D60N) mutation and a second mutation: A291T (612222.0015) and W230X (612222.0016) in 2 of the families, and 1374delT (612222.0017) causing premature termination in a third. W230X and A291T had no residual GALNS activity when overexpressed in cultured cells, whereas D60N had 12.2% residual activity compared with wildtype. The tertiary structural model of the GALNS protein showed that asp60 is located on the surface of the molecule, away from the active site. On the other hand, ala291 and trp230 are localized near the active site. The molecular characteristics of the D60N mutation explained the attenuated clinical phenotype of the patients. The oldest patient was 9 years of age, and the youngest 3 years.
See 612222.0014 and Montano et al. (2003).
See 612222.0014 and Montano et al. (2003).
See 612222.0014 and Montano et al. (2003).
In 5 of 24 Chinese patients with MPS IVA (253000), Wang et al. (2010) identified a 1019G-A transition in exon 10 of the GALNS gene, resulting in a gly340-to-asp (G340D) substitution. Three patients were homozygous, and 2 patients were compound heterozygous for G340D and another mutation. G340D was the most common mutant allele, accounting for 16.7% of the total number of mutant alleles. Haplotype analysis indicated a founder effect, and all 5 patients were residents of or emigrants from central eastern China.
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