Alternative titles; symbols
HGNC Approved Gene Symbol: ARSG
Cytogenetic location: 17q24.2 Genomic coordinates (GRCh38): 17:68,259,170-68,452,019 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q24.2 | Usher syndrome, type IV | 618144 | Autosomal recessive | 3 |
Arylsulfatase G is a critical lysosomal enzyme that functions in the degradation of heparan sulfate by removing terminal N-sulfoglucosamine-3-O-sulfate residues from the nonreducing end (Kowalewski et al., 2012).
By sequencing clones obtained from a size-fractionated human brain cDNA library, Nagase et al. (1999) cloned ARSG, which they designated KIAA1001. The cDNA contains several repetitive elements in its 3-prime UTR, and the deduced 525-amino acid protein shares 39.7% amino acid identity with arylsulfatase A precursor (ARSA; 607574). RT-PCR ELISA detected highest expression in brain, ovary, spleen, testis, and spinal cord, lower expression in heart, lung, liver, skeletal muscle, kidney, fetal liver, and fetal brain, and little to no expression in pancreas. Among specific adult brain regions examined, highest expression was in cerebellum, thalamus, and subthalamic nuclei.
By searching databases for sequences similar to sulfatases, Ferrante et al. (2002) identified ARSG. The deduced 525-amino acid protein contains 10 residues in its putative catalytic site conserved among all sulfatases and 4 putative N-glycosylation sites. Northern blot analysis detected low, ubiquitous ARSG expression, with highest levels in pancreas, kidney, and brain. In situ hybridization of mouse embryos also revealed low, ubiquitous expression. Western blot analysis of transfected COS-7 cells detected ARSG at an apparent molecular mass of 70 kD, and endoglycosidase treatment reduced the mass to 62 kD, suggesting that all 4 N-glycosylation sites are used. Immunofluorescence microscopy detected ARSG colocalized with endoplasmic reticulum markers.
Sardiello et al. (2005) determined that all human sulfatases, including ARSG, have 9 regions of strong evolutionary conservation, most of which contain residues involved in the sulfatase hydrolysis reaction.
Using immunohistochemical analysis, Frese et al. (2008) found that overexpression of human ARSG in a fibrosarcoma cell line resulted in localization of ARSG to the perinuclear region and to vesicular spots that colocalized with markers of lysosomes.
By PCR analysis of 17 different human tissues, Khateb et al. (2018) found that ARSG was expressed in most of the tissues, including the retina.
Ferrante et al. (2002) determined that the ARSG gene contains 11 exons and spans 95.6 kb.
By genomic sequence analysis, Ferrante et al. (2002) mapped the ARSG gene to chromosome 17q23-q24. Sardiello et al. (2005) stated that the ARSG gene maps to chromosome 17q24.2.
Kowalewski et al. (2014) characterized the processing of mouse liver Arsg, which is synthesized as a 524-amino acid pre-precursor protein with a predicted 16-amino acid signal peptide. Their work indicated that, in the endoplasmic reticulum (ER), the signal peptide is cleaved off cotranslationally, cys84 is modified to formylglycine, and 4 asparagine residues are modified with N-glycans, resulting in a protein with an apparent molecular mass of 63 kD. In the Golgi, the N-glycans are at least partially modified, and asn497 is modified with mannose 6-phosphate. En route to late endosomes/lysosomes, proteolytic processing yields fragments of 44 and 18 kD; the 44-kD fragment is then cleaved by cathepsins B (CTSB; 116810) and L (CTSL; 116880) into 34- and 10-kD chains. The 18- and 10-kD chains are linked by a disulfide bond. Both the 63-kD ER form and 34-kD lysosomal form of Arsg were catalytically active in vitro against a synthetic substrate.
By database analysis, Frese et al. (2008) determined that the human ARSG clone KIAA1001 contained a pro501 codon, whereas wildtype mouse and human ARSG contained ala501. They found that purified wildtype ARSG showed high arylsulfatase activity against synthetic substrates at acidic pH and that the A501P substitution significantly reduced its arylsulfatase activity. Characterization of wildtype ARSG revealed a pH optima of 5.4 to 5.6 and thermostability. ARSG was competitively inhibited by phosphate, with weaker inhibition by sulfate. Mutation analysis revealed that cys84, which was predicted to be posttranslationally modified to formylglycine, was required for ARSG activity. In vitro, ARSG bound to immobilized mannose-6-phosphate receptors (M6PR; 154540), which deliver lysosomal proteins to lysosomes.
Kowalewski et al. (2012) demonstrated that lysosomal ARSG is a sulfatase specific for 3-O-sulfated N-sulfoglucosamine (GlcNS3S) residues at the nonreducing ends (NREs) of heparan sulfate chains. ARSG is essential for the catabolism of heparan sulfate, as evidenced by the resulting heparan sulfate storage and mucopolysaccharidosis disease pathology in Arsg-knockout mice (see ANIMAL MODEL).
In 5 affected members of 3 consanguineous Yemenite Jewish families with an atypical form of Usher syndrome (USH4; 618144), Khateb et al. (2018) identified homozygosity for a missense mutation in the ARSG gene (D45Y; 610008.0001). The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the families. All haplotypes surrounding the variant were identical, indicating that it is a founder mutation. The mutation was found in heterozygous state in 1 of 101 Yemenite Jewish controls, corresponding to a minor allele frequency of 0.005, and was not found in the gnomAD database.
Abad-Morales et al. (2020) identified a homozygous mutation in the ARSG gene (D44N; 610008.0002) in a 44-year-old Spanish woman with USH4. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing.
Peter et al. (2021) reported 2 Portuguese patients with USH4 and mutations in the ARSG gene. Individual 1 (LL64) had a homozygous mutation (610008.0003) and individual 2 (LL197) had compound heterozygous mutations (610008.0004-610008.0005). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. All 3 mutations were shown to abolish acid sulfatase activity and to lead to protein mislocalization to the endoplasmic reticulum.
In a 60-year-old Persian man with USH4, Fowler et al. (2021) identified a homozygous mutation in the ARSG gene (R424C; 610008.0006).
In 3 unrelated patients with USH4, Velde et al. (2022) identified compound heterozygous mutations in the ARSG gene, including 5 novel mutations (610008.0007-610008.0011) and 1 previously reported mutation (610008.0003). Expression of ARSG with each mutant in HT1080 cells resulted in decreased sulfatase activity compared to wildtype.
Abitbol et al. (2010) found that adult-onset cerebellar ataxia in American Staffordshire terrier (AST) dogs is a form of neuronal ceroid lipofuscinosis (CLN, see, e.g., 256730). The phenotype of 138 affected ASTs from France and the United States was characterized by locomotor disability manifest as static and dynamic ataxia with loss of balance and stumbling when turning corners, walking uphill or downhill, or negotiating stairs. Most (70%) dogs first displayed locomotor ataxia between 3 and 5 years of age. Brain MRI in 58 dogs showed significant cerebellar atrophy, which was confirmed by postmortem analysis. Histologic findings revealed a marked loss of Purkinje cells, with remaining neuronal cells containing PAS-, Luxol fast blue-, and Sudan black-positive cytoplasmic material suggestive of lipofuscin accumulation. Ultrastructural studies showed abnormal lysosomes filled with electron-dense inclusions in curved, straight, or concentric profiles. None of the dogs had visual defects. Linkage analysis mapped the disorder to canine chromosome 9, which is syntenic to human chromosome 17, and a homozygous 296G-A transition (arg99 to his, R99H) was identified in the Arsg gene in all affected animals. A heterozygous mutation was found in 50% of healthy dogs, consistent with a carrier state. Expression of the mutation in HEK293T cells showed that the mutant protein had only 18.1% activity compared to controls, and leukocytes derived from affected dogs showed significantly decreased Arsg activity compared to wildtype. Abitbol et al. (2010) suggested that the human ARSG gene may be candidate for human adult-onset CLN, also known as Kufs disease (see, e.g., CLN4A, 204300).
Kowalewski et al. (2012) found that Arsg -/- mice developed normally, showed no obvious change in appearance, and were fertile. However, after 12 months of age, Arsg -/- mice showed progressive deficit in exploratory behavior and age-dependent cognitive impairment in learning tasks. Mutant mice accumulated heparan sulfate in lysosomes of visceral organs and central nervous system with neuronal cell death. The nonreducing end of accumulated heparan sulfate exhibited N-sulfoglucosamine-3-O-sulfate residues. Wildtype human ARSG liberated the 3-O-sulfate group from heparan sulfate purified from Arsg -/- liver. Kowalewski et al. (2012) concluded that ARSG is critical in lysosomal catabolism of heparan sulfate.
Kowalewski et al. (2015) detailed expression of Arsg in mouse central nervous system and development of pathology in Arsg -/- mice. Although Arsg was expressed in all regions of the brain, pathologic changes and lysosomal storage were almost exclusively restricted to the cerebellum and perivascular macrophages. Oligodendrocytes expressed high amounts of Arsg, but Arsg -/- mice showed neither storage pathology in oligodendrocytes nor massive demyelination. Kowalewski et al. (2015) also found significant accumulation of free cholesterol in perivascular macrophages, and buildup of gangliosides GM2 and GM3 in Purkinje cell dendrites and phagocytic macrophages, respectively. Purkinje cells showed cytosolic aggregates of autophagy adaptors and ubiquitinated proteins and were the only cell type clearly affected by cell death.
Kruszewski et al. (2016) found that Arsg -/- mice showed progressive degeneration of photoreceptor cells starting between 1 and 6 month of age, resulting in loss of more than 50% of photoreceptor cells in 24-month-old mice. Photoreceptor loss was accompanied by reactive astrogliosis, reactive microgliosis that was evident in the outer but not inner retina, and elevated expression of some lysosomal proteins. Electron microscopic analysis revealed no evidence for storage vacuoles in mutant retinas. Electron microscopic analysis of wildtype retina detected Arsg only in retinal pigment epithelium, which appeared normal in Arsg -/- mice. Kruszewski et al. (2016) concluded that ARSG deficiency can result in progressive photoreceptor degeneration and dysregulation of lysosomal proteins.
In 5 affected members of 3 consanguineous Yemenite Jewish families (MOL0120, MOL0737, TB55) with an atypical form of Usher syndrome (USH4; 618144), Khateb et al. (2018) identified homozygosity for a c.133G-T transversion (c.133G-T, NM_014960.4) in exon 2 of the ARSG gene, resulting in an asp45-to-tyr (D45Y) substitution at a highly conserved residue that forms part of the catalytic pocket of the protein. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the families. All haplotypes surrounding the variant were identical, indicating that it is a founder mutation. The mutation was found in heterozygous state in 1 of 101 Yemenite Jewish controls, corresponding to a minor allele frequency of 0.005, and was not found in the gnomAD database. Expression analysis of the D45Y mutant in human HT1080 cells detected no significant sulfatase activity. There was also a lack of processing of the ARSG precursor protein into its mature 3 chains, suggesting that D45Y mutant is improperly transported to the lysosomes. However, a drastic decrease in the stability of the D45Y precursor protein was not observed.
In a 44-year-old Spanish patient with Usher syndrome type IV (USH4; 618144), Abad-Morales et al. (2020) identified a homozygous c.130G-A transition (c.130G-A, NM_014960.4) in the ARSG gene, resulting in an asp44-to-asn (D44N) substitution at a highly conserved residue. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was present in the ExAC database at a minor allele frequency of 0.00002 and was not found in an in-house cohort of 261 control individuals. Functional studies were not performed.
In a 74-year-old Portuguese woman (individual 1, LL64) with Usher syndrome type IV (USH4; 618144), Peter et al. (2021) identified a homozygous 1-bp deletion (c.1326del, NM_014960.4) in the last exon of the ARSG gene, predicted to result in a frameshift and premature termination (Ser443AlafsTer12). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient's unaffected sib did not carry the mutation and her unaffected daughter was heterozygous for the mutation. The mutation was present in the gnomAD database at a frequency of 0.0000778 and was not present in 14,749 Portuguese individuals. Expression of ARSG with the c.1326del mutation in HeLa cells showed similar expression levels to wildtype but had a lower molecular weight, consistent with a truncated protein. Immunofluorescence studies showed that the mutant protein did not localize correctly to the lysosome, and staining patterns were compatible with localization to the endoplasmic reticulum. Furthermore, the mutant protein did not have acid sulfatase enzyme activity.
In a patient (subject F) with USH4, Velde et al. (2022) identified compound heterozygous mutations in the ARSG gene: c.1326del, and a c.1024C-T transition resulting in an arg342-to-trp (R342W; 610008.0007) substitution. The mutations were identified by whole-genome sequencing. Segregation analysis was not performed. The c.1326del mutation was present in the gnomAD database at a minor allele frequency (%) of 0.007781, and the R342W mutation was present at a minor allele frequency (%) of 0.000796. Sulfatase activity in HT1080 cells transfected with ARSG with the R342R mutation was decreased compared to wildtype ARSG.
In a 60-year-old Portuguese woman (individual 2, LL197) with Usher syndrome type IV (USH4; 618144), Peter et al. (2021) identified compound heterozygous mutations in the ARSG gene: a c.253T-C transition (c.253T-C, NM_014960.4), resulting in a ser85-to-pro (S85P) substitution at a conserved residue, and a c.338G-A transition, resulting in a gly113-to-asp (G113D) substitution at a conserved residue. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The S85P mutation was present in the gnomAD database at a frequency of 0.0000106 and was not present in 14,749 Portuguese individuals; the G113D mutation was present in the gnomAD database at an overall frequency of 0.00000398 and at a frequency of .0000339 in 14,749 Portuguese individuals. Expression of ARSG with the S85P or the G113D mutation in HeLa cells showed similar expression levels to wildtype ARSG. Immunofluorescence studies showed that the mutant proteins did not localize correctly to the lysosome, and staining patterns were compatible with localization to the endoplasmic reticulum. In addition, the mutant proteins did not have acid sulfatase enzyme activity.
For discussion of the c.338G-A transition (c.338G-A, NM_014960.4) in the ARSG gene, resulting in a gly113-to-asp (G113D) substitution, that was found in compound heterozygous state in a patient with Usher syndrome type IV (USH4; 618144) by Peter et al. (2021), see 610008.0004.
In a 60-year-old Persian man with Usher syndrome type IV (USH4; 618144), Fowler et al. (2021) identified a homozygous c.1270C-T transition in the ARSG gene, resulting in an arg424-to-cys (R424C) substitution. The variant was not present in the gnomAD database. Protein modeling suggested that the R424C mutation leads to protein instability due to loss of a specific electrostatic interaction.
For discussion of the c.1024C-T transition (c.1024C-T, NM_014960.5) in the ARSG gene, resulting in an arg342-to-trp (R342W) substitution, that was identified in compound heterozygous state in a patient (subject F) with Usher syndrome type IV (USH4; 618144) by Velde et al. (2022), see 610008.0003.
In a patient (subject N) with Usher syndrome type IV (USH4; 618144), Velde et al. (2022) identified compound heterozygous mutations in the ARSG gene: a c.1212+1G-A transition (c.1212+1G-A, NM_014960.5), resulting in a splicing defect, and a c.275T-C transition, resulting in a leu92-to-pro (L92P; 610008.0009) substitution. The mutations were identified by whole-exome sequencing, and segregation analysis determined that the mutations were in trans. The c.1212+1G-A mutation was not present in the gnomAD database, and the L92P mutation was present with a minor allele frequency (%) of 0.000398. A minigene assay showed that the c.1212+1G-A mutation resulted in use of an alternative splice site, resulting in a frameshift and premature termination (Val405IlefsTer41). Sulfatase activity in HT1080 cells transfected with ARSG with the L92P mutation was decreased compared to wildtype ARSG.
For discussion of the c.275T-C transition (c.275T-C, NM_014960.5) in the ARSG gene, resulting in a leu92-to-pro (L92P) substitution, that was identified in compound heterozygous state in a patient (subject N) with Usher syndrome type IV (USH4; 618144) by Velde et al. (2022), see 610008.0008.
In a patient (subject D) with Usher syndrome type IV (USH4; 618144), Velde et al. (2022) identified compound heterozygous mutations in the ARSG gene: a c.588C-A transversion (c.588C-A, NM_014960.5), resulting in a tyr196-to-ter (Y196X; 610008.0010) substitution, and a deletion spanning exons 7 and 8 (c.705-3940_982+2952del; 610008.0011), resulting in a frameshift and premature termination (Ser235ArgfsTer29). The mutations, which were identified by whole-genome sequencing and confirmed by Sanger sequencing, were shown to be in trans. The Y196X mutation was present in the gnomAD database at an allele frequency (%) of 0.000396 and the c.705-3940_982+2952del mutation was not present in gnomAD. Expression of each mutation in HT1080 cells resulted in decreased sulfatase activity compared to wildtype.
For discussion of the deletion of exons 7 and 8 (c.705-3940_982+2952del, NM_014960.5) of the ARSG gene, resulting in a frameshift and premature termination (Ser235ArgfsTer29), that was identified in compound heterozygous state in a patient (subject D) with Usher syndrome type IV (USH4; 618144) by Velde et al. (2022), see 610008.0010.
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