Alternative titles; symbols
HGNC Approved Gene Symbol: SGSH
SNOMEDCT: 41572006; ICD10CM: E76.22;
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38) : 17:80,200,673-80,220,333 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Mucopolysaccharidosis type IIIA (Sanfilippo A) | 252900 | Autosomal recessive | 3 |
Scott et al. (1995) reported the isolation, sequence, and expression of cDNA clones encoding N-sulfoglucosamine sulfohydrolase, the enzyme deficient in mucopolysaccharidosis IIIA (MPS3A; 252900), also known as Sanfilippo syndrome A. By micropeptide sequence analysis, followed by screening of a cDNA kidney library, they isolated a cDNA encoding a 502-amino acid sulfamidase protein. Sequence analysis predicted that the 482-amino acid mature protein contains 5 potential N-glycosylation sites. Northern blot analysis revealed expression of 3.1-, 4.3-, and 7.1-kb transcripts that are variably expressed in all tissues except brain.
By SDS-PAGE analysis, Bielicki et al. (1998) determined that recombinant and native sulfamidase is expressed in CHO cells as a 115-kD dimer with an approximately 63-kD major subunit and an approximately 57-kD minor subunit with identical N-terminal residues after cleavage of the leader peptide. Kinetic analysis showed that the recombinant enzyme has similar parameters to the native type and is endocytosed by MPS IIIA fibroblasts via the mannose 6-phosphate receptor (see 154540), suggesting that the recombinant sulfamidase may be a suitable candidate for enzyme replacement therapy.
Costanzi et al. (2000) isolated and sequenced the mouse Sgsh gene.
Karageorgos et al. (1996) determined the structure of the SGSH gene and the sequence of the exon/intron boundaries and the 5-prime promoter region. The gene contains 8 exons spanning approximately 11 kb.
Karageorgos et al. (1996) isolated a genomic clone containing the entire sulfamidase gene from a chromosome 17-specific gridded cosmid library.
By fluorescence in situ hybridization, Scott et al. (1995) mapped the sulfamidase gene to 17q25, with 17q25.3 as the most likely localization. They suggested that a (1;21) balanced translocation reported by Rodewald et al. (1980) in a patient with MPS IIIA was an incidental finding.
Costanzi et al. (2000) found that the mouse Sgsh gene maps to the distal end of chromosome 11, in a region that is homologous with a segment of human chromosome 17 containing the orthologous human gene.
In 2 unrelated patients with mucopolysaccharidosis type IIIA (MPS3A; 252900), also known as Sanfilippo syndrome A, Scott et al. (1995) identified an 11-bp deletion in sulfamidase cDNA (605270.0008).
Blanch et al. (1997) investigated molecular defects in the sulfamidase gene in 10 patients with MPS3A of Australian and American origin. The entire coding region of the gene was RT-PCR amplified and 1 polymorphism, 4 novel mutations (S66W, 605270.0003; R245H, 605270.0001; E447K, 605270.0006; and 1307del9, 605270.0007), and 1 previously described mutation (1284del11, 605270.0008) were identified by PCR sequencing. R245H was present in 6 patients, including 1 severely affected homozygote. In 3 of the other patients with R245H, second mutant alleles were identified as S66W, 1284del11, and E447K.
In a mutation screen of 42 European patients with MPS3, Bunge et al. (1997) identified 17 different mutations, of which 16 were novel. A missense mutation (R74C; 605270.0002) that altered an evolutionarily conserved amino acid in the active site of the sulfamidase enzyme was found on 56% of alleles of 16 Polish patients, whereas it was less frequent (21% of disease alleles) among German patients. R245H, a common mutation reported by Blanch et al. (1997), represented 35% of disease alleles in German patients, but only 3% in Polish patients.
Di Natale et al. (1998) characterized 38 (79%) pathogenic alleles in 24 Italian MPS IIIA patients. They identified 16 different molecular defects, of which 13 were novel. Most were missense mutations. Two single basepair deletions and a basepair insertion were also identified. The previously identified S66W substitution (605270.0003) represented the most common alteration, accounting for 33% of total alleles. All 6 patients from Sardinia had this mutation and 5 of them were homozygous for the change, suggesting that these patients may share a common ancestor.
Esposito et al. (2000) reported 2 novel mutations and stated that approximately 40 mutations of the heparan N-sulfatase gene leading to MPS IIIA had been described. In expression studies of 15 of the mutations, none yielded active enzyme. Western blot analysis and metabolic labeling experiments revealed, for cells transfected with wildtype enzyme, a precursor 62-kD form and a mature 56-kD form. For 11 of the 15 mutations, Western blot analysis resulted in the demonstration of both forms, indicating a normal maturation of the mutant enzyme. For the other 4 mutations, studies indicated increased degradation of the mutant enzymes.
Yogalingam and Hopwood (2001) reported that 62 mutations in the SGSH gene causing MPS IIIA had been defined: 46 missense/nonsense mutations, 15 small insertions/deletions, and 1 splice site mutation. Most of the mutations identified in SGSH, and in NAGLU (609701) in MPS IIIB (252920), are associated with severe clinical phenotypes.
In 2 Chinese patients with MPS IIIA, Lee-Chen et al. (2002) identified 4 missense mutations (both were compound heterozygotes) and 5 polymorphisms in the SGSH gene. The polymorphic haplotype of the SGSH gene was analyzed in 52 unrelated subjects. All 5 polymorphisms were in Hardy-Weinberg equilibrium. The strong nonrandom association among the 5 polymorphisms suggested that there is little or no recombination in the SGSH gene.
Di Natale et al. (2003) described a large pedigree in which 2 second cousins had Sanfilippo syndrome A caused by mutations in the SGSH gene: 1 cousin, with severe disease, was a compound heterozygote for the mutations glu369 to lys (E369K; 605270.0009) and arg433 to gln (R433Q; 605270.0010); the other, with a mild form of the disorder, was a compound heterozygote for the mutations E369K and pro128 to leu (P128L; 605270.0011).
Gabrielli et al. (2005) reported an Italian woman with a mild form of Sanfilippo syndrome A caused by a homozygous mutation in the SGSH gene (R206P; 605270.0012).
Valstar et al. (2010) retrospectively reviewed the clinical features of 92 patients with MPS IIIA, including 32 living and 60 deceased individuals. There was wide phenotypic variability that correlated with genotype. In particular, those with 1 or more S298P (605270.0013) mutant alleles had an attenuated phenotype, with a significantly longer preservation of psychomotor functions and a longer survival. The most frequent pathogenic mutations were R245H (605270.0001), Q380R, S66W (605270.0003), and 1080delC, all of which were associated with the classic severe phenotype.
Bhattacharyya et al. (2001) described a spontaneous mouse mutant of MPS IIIa resulting from a homozygous asp31-to-asn (D31N) mutation in the murine sulfatase gene. Affected mice died at about 10 months of age exhibiting a distended bladder and hepatosplenomegaly. Brain sections show distended lysosomes, some with typical zebra body morphology, and many containing periodic acid-Schiff-positive storage material. Urinalysis revealed an accumulation of heparan sulfate. Assays of a variety of lysosomal hydrolases in brain, liver, and kidney extracts uncovered a specific defect in sulfamidase activity, which was reduced by about 97%.
Saville and Fuller (2020) studied lipid content in the brains of a naturally occurring mouse model of MPS IIIA at 1 and 6 months of age. Heparin sulfate (HS) disaccharide levels were increased in the mutant mice compared to controls across all 4 brain regions that were evaluated (brainstem, cortex, cerebellum and subcortex) at 1 month of age. At 6 months of age, HS disaccharide levels were increased in the cortex and subcortex regions compared to mutant mice at 1 month of age, but levels in the cerebellum were unchanged. There was a significantly higher level of GM2 gangliosides in the mutant mice compared to controls at 1 month of age in all brain regions except the cortex, and the level was highest in the brainstem. At 6 months of age, GM2 levels were increased in all brain regions compared to controls and 1-month-old mutant mice. GM3 levels were elevated in the brainstem and subcortex of 1-month-old mutant mice compared to controls. At 6 months of age, GM3 levels were significantly elevated in all brain regions compared to both 1-month-old mutant mice and controls. Saville and Fuller (2020) concluded that alterations in ganglioside metabolism and sphingolipid metabolism differed by age and brain region in the naturally occurring mouse model of MPS IIIA.
In a mouse model of MPS IIIA, Intartaglia et al. (2020) demonstrated progressive decrease of retinal function with a gradual loss of cones starting at 3 months of age and culminating in severe retinal dysfunction at 9 months of age. This was accompanied by an inflammatory microglial cell response and increased apoptotic cell death in the retinal outer nerve layer by 9 months of age. Intartaglia et al. (2020) also found increased heparan sulfate in the retinal cells correlating to a block in lysosomal-autophagosomal fusion and consistent with defective autophagy.
Tillo et al. (2022) investigated the etiology of cachexia in a mouse model of MPS IIIA. The mutant mice had increased intestinal uptake of dietary triglyceride (triolein) and fasting and postprandial hypertriglyceridemia compared to wildtype mice. This correlated to increased uptake of triolein into brown adipose tissue, followed by hyperthermia, increased eating and drinking, and increased energy expenditure. Mutant mice who were treated with a lipolytic inhibitor were cold intolerant, suggesting that they were unable to generate energy from endogenous stored lipids and were instead reliant on exogenous lipids for fuel. The brown adipose tissue in the mutant mice also had increased mitochondrial content resulting from abnormal lysosomal-autophagosome fusion, and Tillo et al. (2022) hypothesized that this impaired autophagy led to increased energy expenditure in brown adipose tissue. Postprandial hypertriglyceridemia was ameliorated by enzyme replacement therapy with sulfamidase.
In 6 of 10 Australian and American patients with mucopolysaccharidosis type IIIA (MPS3A; 252900), also known as Sanfilippo syndrome A, Blanch et al. (1997) demonstrated that at least 1 allele of the sulfamidase gene carried a G-to-A transition at nucleotide position 746, changing arginine-245 to a histidine (R245H). This missense mutation was present in 7 of 20 alleles from the 6 patients, including 1 patient homozygous for R245H.
In the Netherlands, Weber et al. (1998) found that the R245H mutation accounted for 56.7% of the Sanfilippo A alleles. The R245H allele had a higher prevalence in western than in eastern regions of the Netherlands. Of 39 MPS III patients, for whom they had uniform clinical data, 13 patients who were homozygous for this common mutation had a more uniform but severe clinical phenotype than the remaining 21 or 5 patients, with, respectively, 1 or no R245H alleles.
Bunge et al. (1997) found that the missense mutation arg74-to-cys (R74C), which alters an evolutionarily conserved amino acid in the active site of the sulfamidase enzyme, was present in 56% of SGSH alleles of 16 Polish patients with mucopolysaccharidosis type IIIA (MPS3A; 252900), whereas it was less frequent (21% of disease alleles) among German patients. The R245H mutation (605270.0001) represented 35% of disease alleles in German patients, but only 3% in Polish patients. Because the combined frequency of the common mutations R74C and R245H in German and Polish populations exceeded 55%, Bunge et al. (1997) suggested that screenings for these 2 mutations would assist molecular genetic diagnosis of MPS IIIA and allow heterozygote testing in these populations.
Among 24 Italian mucopolysaccharidosis IIIA (MPS3A; 252900) patients, Di Natale et al. (1998) identified a ser66-to-trp (S66W) missense mutation in the SGSH gene, accounting for 33% of all mutant alleles. All 6 patients from Sardinia had this mutation and 5 of them were homozygous for the change, suggesting that they may share a common ancestor. Montfort et al. (1998) found the S66W mutation in exon 2 in compound heterozygous state in a Spanish patient with Sanfilippo syndrome A.
Di Natale et al. (1999) reported the prenatal diagnosis of Sanfilippo syndrome A by study of chorionic villi in the 11-week-old fetus of a woman who was homozygous for the S66W mutation. Because of the findings, the pregnancy was terminated at 12 weeks' gestation.
Montfort et al. (1998) presented mutation analysis and clinical findings in 11 Spanish patients with mucopolysaccharidosis type IIIA (MPS3A; 252900) in whom 19 of the 22 mutant alleles had been identified. Seven different mutations were found, of which 4 had not previously been described. The most frequent mutation was a 1-bp deletion (C) at nucleotide 1091 which accounted for nearly one-half of the mutated alleles. It was present in homozygous state in 3 patients and in compound heterozygous state in 3 patients. Mutations R74C (605270.0002) and R245H (605270.0001) were not found in this study.
In a study in Barcelona, Chabas et al. (2001) found that chromosomes bearing the 1091delC mutation showed a conserved haplotype, suggesting a common origin for this mutation.
In a Spanish patient with mucopolysaccharidosis type IIIA (MPS3A; 252900), Montfort et al. (1998) found an arg150-to-glu (R150Q) mutation in exon 4 of the SGSH gene. The same mutation had previously been identified by Di Natale et al. (1998).
In a patient with mucopolysaccharidosis type IIIA (MPS3A; 252900), Blanch et al. (1997) found a G-to-A transition at nucleotide 1351 of the SGSH gene, which resulted in a glu447-to-lys (E447K) amino acid substitution. They found this mutation in compound heterozygosity with the R245H mutation (605270.0001).
In a patient with mucopolysaccharidosis type IIIA (MPS3A; 252900), Blanch et al. (1997) found a 9-bp deletion of the SGSH gene, beginning at nucleotide 1307. This deletion resulted in the last 2 bases of codon 432 being changed from AC to GC, leading to a tyrosine-to-tryptophan substitution (Y432W). Additionally, the next 3 amino acids (arg433, ala434, and arg435) were deleted before restoration of the normal reading frame at trp436.
In a patient with mucopolysaccharidosis type IIIA (MPS3A; 252900), Blanch et al. (1997) found an 11-bp deletion of the SGSH gene, beginning at nucleotide 1284. This deletion resulted in a change of the last base of codon 424 from C to G, altering the original tyrosine to a stop codon and leading to a 78-amino acid shortened sulfamidase.
Scott et al. (1995) identified this mutation in sulfamidase cDNA from 2 unrelated patients with Sanfilippo syndrome A.
In 2 second cousins from a large family, Di Natale et al. (2003) showed that mucopolysaccharidosis type IIIA (MPS3A; 252900) was caused by compound heterozygosity for 2 mutations in the SGSH gene: in 1 cousin, with severe disease, the mutations were glu369 to lys (E369K) and arg433 to gln (R433Q; 605270.0010); in the other, with the attenuated form of the disease, the mutations were E369K and pro128 to leu (P128L; 605270.0011). Di Natale et al. (2003) identified R433Q as a severe mutation underlying Sanfilippo syndrome A.
For discussion of the arg433-to-gln (R433Q) mutation in the SGSH gene that was found in compound heterozygous state in a patient with Sanfilippo syndrome A (252900) by Di Natale et al. (2003), see 605270.0009.
For discussion of the pro128-to-leu (P128L) mutation in the SGSH gene that was found in compound heterozygous state in a patient with the attenuated form of mucopolysaccharidosis type IIIA (MPS3A; 252900) by Di Natale et al. (2003), see 605270.0009.
In a patient with the attenuated form of mucopolysaccharidosis type IIIA (MPS3A; 252900), Gabrielli et al. (2005) identified a homozygous mutation in exon 5 of the SGSH gene, resulting in an arg206-to-pro (R206P) substitution. Biochemical studies showed that the mutant enzyme retained 8% residual activity. The patient had moderate mental retardation without behavioral abnormalities.
In a patient with mucopolysaccharidosis type IIIA (MPS3A; 252900), Bunge et al. (1997) identified an 892T-C transition in the SGSH gene, resulting in a ser298-to-pro (S298P) substitution.
Meyer et al. (2008) identified the S298P mutation in 10 patients with the attenuated form of MPS IIIA. These patients showed a lower frequency and later onset of the typical symptoms of the disease. The onset of regression in speech abilities and cognitive functions was delayed by 0.7 and 0.8 years, respectively, and the onset of regression of motor functions occurred 6.1 years later than in all other MPS IIIA patients. Severe regression in speech, cognitive and motor functions were delayed by 5, 5.9, and 11.2 years, respectively. The findings suggested that the S298P allele is associated with a slowly progressive phenotype.
Valstar et al. (2010) also provided evidence that the S298P mutation is associated with an attenuated form of MPS IIIA in several patients from the Netherlands.
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