* 611542

ARYLSULFATASE B; ARSB


HGNC Approved Gene Symbol: ARSB

Cytogenetic location: 5q14.1     Genomic coordinates (GRCh38): 5:78,777,209-78,985,958 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
5q14.1 Mucopolysaccharidosis type VI (Maroteaux-Lamy) 253200 AR 3

TEXT

Description

The ARSB gene encodes arylsulfatase B (N-acetylgalactosamine 4-sulfatase; EC 3.1.6.12), a lysosomal enzyme that removes the C4 sulfate ester group from the N-acetylgalactosamine sugar residue at the nonreducing terminus of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin sulfate during lysosomal degradation (Karageorgos et al., 2007).


Cloning and Expression

Schuchman et al. (1990) cloned a full-length ARSB cDNA from a human testes cDNA library. The deduced 533-residue protein has 6 potential N-glycosylation sites. Comparison of the predicted amino acid sequences of arylsulfatases A (ARSA; 607574), B, and C (ARSC; 300747) demonstrated regions of identity, particularly in their N termini.

Kunieda et al. (1995) isolated the rat Arsb gene.


Gene Structure

The ARSB gene contains 8 exons and spans about 206 kb (Karageorgos et al., 2007).


Mapping

Hellkuhl and Grzeschik (1978) assigned a gene for arylsulfatase B to chromosome 5 by human-mouse somatic cell hybrids. By somatic cell hybridization methods, DeLuca et al. (1979) assigned arylsulfatases A and B to chromosomes 22 and 5, respectively. By study of an interstitial deletion of 5q12, Dudin et al. (1984) excluded ARSB and HEXB from this segment.

Fidzianska et al. (1984) assigned the ARSB locus to 5p11-qter by analysis of somatic cell hybrids isolated from 2 separate fusions of human fibroblasts carrying a translocation involving chromosome 5 with a Chinese hamster cell line. By study of rearranged chromosomes in human/hamster hybrids, using a tritium-labeled human genomic DNA fragment for in situ hybridization, Fidzianska et al. (1986) narrowed the assignment of ARSB to 5q11-q13.

Litjens et al. (1989) localized the ARSB gene to 5q13-q14.

By rat/mouse somatic cell hybridization, Kunieda et al. (1995) localized the rat Arsb gene to chromosome 2.


Molecular Genetics

In a patient with mucopolysaccharidosis type VI (253200), Wicker et al. (1991) identified a homozygous mutation in the ARSB gene (611542.0001).

In patients with MPS VI, Jin et al. (1992) identified homozygous or compound heterozygous mutations in the ARSB gene (611532.0002-611542.0004).

In 9 patients with MPS VI, Litjens et al. (1996) identified several mutations in the ARSB gene (see, e.g., 611542.0008-611542.0010). All patients were compound heterozygotes and showed variable phenotypes ranging from mild to severe. For each patient, the combined biochemical phenotypes of the 2 mutant sulfatase alleles demonstrated a good correspondence with the observed clinical phenotype.

Litjens and Hopwood (2001) stated that a total of 45 clinically relevant mutations had been identified in the ARSB gene in patients with mucopolysaccharidosis type VI. Missense mutations represented the largest group, with 31 identified. No common mutations had been described, making screening of the general population difficult.

Karageorgos et al. (2007) identified 83 different ARSB mutations among 105 patients with MPS VI. The most frequent mutation was Y210C (611542.0009), which was identified in 18% of patients and associated with an attenuated phenotype.

Among 12 Spanish and 4 Argentinian patients with MPS VI, Garrido et al. (2007) identified 19 different mutations, including 9 novel mutations, in the ARSB gene. The most common mutant alleles were splice site mutations, 611542.0011 and 611542.0012, which accounted for 21.9% and 12.5% of mutant alleles, respectively.

Tomanin et al. (2018) reviewed all variants in the ARSB gene in patients with MPS VI reported in the literature and in public databases and identified 908 alleles with 198 distinct nonpolymorphic variants from 478 patients. They also identified 3 benign variants that had previously been incorrectly reported as pathogenic. Most (59.5%) unique variants were missense, followed by small deletions (13.5%), nonsense (12.0%), splice site or intronic (5.0%), small duplications (3.0%), and large deletions (3.0%). Of the unique alleles, 31.7% appeared only once, with an additional 28.5% appearing twice. Of the identified patients, 54.8% were homozygous for pathogenic ARSB variants, 35.6% were heterozygous, 9.2% had only one allele reported, and 0.4% had both alleles unidentified. Pathogenic variants in ARSB did not appear to be concentrated in any particular region of the protein. Analysis of the genotype-phenotype correlation based on homozygotes was poorly informative for most variants, although some variants did appear to be associated with a more rapidly progressive phenotype. The authors emphasized the importance of submitting variants to public databases.


Animal Model

Yoshida et al. (1993) reported the clinical, morphologic, and biochemical features of a rat model of MPS VI. Affected rats had facial dysmorphia, dysostosis multiplex, and increased urinary excretion of glucosaminoglycans. Ultrastructural studies revealed storage of GAGs throughout the reticuloendothelial cells, cartilage, and other connective tissues, but no deposition was observed in the nervous system. Biochemical analyses demonstrated that the excreted GAG was dermatan sulfate and the activity of hepatic arylsulfatase B was less than 5% of the normal mean value. Pedigree analysis showed that the phenotype was inherited as an autosomal recessive single trait. Yoshida et al. (1994) demonstrated that the responsible gene lies on rat chromosome 2. It had been known that some loci on rat chromosome 2 correspond to those on human chromosome 5 and mouse chromosome 13. Kunieda et al. (1995) demonstrated furthermore MPS VI in rats was due to a homozygous 1-bp insertion (507insC) in the Arsb gene, resulting in a frameshift and premature termination at codon 258.

Evers et al. (1996) produced a targeted disruption of the Arsb gene in mice and found that homozygous mutant animals exhibited arylsulfatase B enzyme deficiency and elevated urinary secretion of dermatan sulfate. They developed progressive symptoms resembling those of MPS VI in humans. Around 4 weeks of age, facial dysmorphism became overt, long bones were shortened, and pelvic and costal abnormalities were observed. Major alterations in bone formation with perturbed cartilaginous tissues in newborns and widened, perturbed, and persisting growth plates in adult animals were seen. All major parenchymal organs showed storage of glycosaminoglycans preferentially in interstitial cells and macrophages. Affected mice were fertile and mortality was not elevated up to 15 months of age.

McGovern et al. (1985) studied the mutant arylsulfatase B enzymes in homozygotes for separately ascertained cat lines with MPS VI. They showed that the enzymes were distinguishable in physicokinetic and immunologic properties as well as in ability to dimerize with normal enzyme in heterozygotes.

Yogalingam et al. (1996) studied the Arsb (feline f4S) gene in MPS VI Siamese cats. They cloned the gene from a normal feline heart cDNA library, sequenced it, and identified a missense mutation (leu476pro; L476P) in the gene in MPS VI cats. Expression of the normal f4S gene, accompanied by mannose-6-phosphate (M6P), corrected the lysosomal storage of undegraded sulfated glycosaminoglycans in these cells. The observation suggested that expression of the normal f4S gene in MPS VI myoblasts is predominantly mediated by an M6P receptor (154540).

Crawley et al. (1996) used a feline model of MPS VI to investigate enzyme replacement therapy. They evaluated tissue distribution and clinical efficacy of 3 forms of recombinant human N-acetylgalactosamine-4-sulfatase. Intravenously administered enzyme was rapidly cleared from the circulation. The majority of the enzyme was distributed to the liver but was also detected in most other tissues. Tissue half-life was approximately 2-4 days. In 3 MPS VI cats, regular intravenous infusions of recombinant enzyme for up to 20 months showed variable reduction of storage vacuoles in Kupffer cells and connective tissues; however, cartilage chondrocytes remained vacuolated. Vertebral bone mineral volume was improved in 2 MPS VI cats in which therapy was initiated before skeletal maturity, and increased bone volume appeared to correlate with earlier age of onset of therapy. One cat showed greater mobility in response to therapy. Crawley et al. (1996) suggested that, given their results, significant reduction in disease progression and tissue pathology might be expected in patients with this disorder.

Crawley et al. (1997) reported a dose-related response effect of enzyme replacement therapy in MPS VI cats treated from birth. The evidence came from clinical, biochemical, and histopathologic observations.

Crawley et al. (1998) stated that the family of cats with MPS VI used for testing the efficacy of enzyme replacement therapy were homozygous for the L476P substitution in the Arsb gene. An additional mutation, asp520asn (D520N), inherited independently from L476P and identified in the same family of cats, resulted in 3 clinical phenotypes: L476P homozygotes exhibited dwarfism and facial dysmorphia due to epiphyseal dysplasia, abnormal low leukocyte 4S/beta-hexosaminidase ratios, dermatan sulfaturia, lysosomal inclusions in most tissues (including chondrocytes), corneal clouding, degenerative joint disease, and abnormal leukocyte inclusions. Similarly, D520N/D520N and L476P/D520N cats had abnormally low leukocyte 4S/beta-hexosaminidase ratios, mild dermatan sulfaturia, lysosomal inclusions in some chondrocytes, and abnormal leukocyte inclusions; however, both had normal growth and appearance. In addition, L476P/D520N cats had a high incidence of degenerative joint disease. Crawley et al. (1998) concluded that L476P/D520N cats have a very mild MPS VI phenotype not previously described in MPS VI humans. Yogalingam et al. (1998), from the same group, also reported biochemical and clinical assessment of L476P homozygous, D520N/L476P compound heterozygous, and D520N homozygous cats. They showed that the entire range of clinical phenotypes, from severe MPS VI, to mild MPS VI, to normal were clustered within a narrow range of residual 4S activity from 0.5 to 4.6% of normal levels. The results suggested that the D520N mutation causes a rapid degradation of 4S protein. The effect of this is partially ameliorated as a result of a significant elevation in the specific activity of mutant D520N 4S reaching the lysosomes.


ALLELIC VARIANTS ( 12 Selected Examples):

.0001 MUCOPOLYSACCHARIDOSIS, TYPE VI, INTERMEDIATE

ARSB, GLY137VAL
  
RCV000000925...

In a patient with mucopolysaccharidosis type VI (MPS6; 253200), born of consanguineous parents, Wicker et al. (1991) identified a homozygous 410G-T transversion in the ARSB gene, resulting in a gly137-to-val (G137V) substitution. The mutation did not affect protein synthesis, but severely reduced protein stability. The phenotype was of intermediate severity.


.0002 MUCOPOLYSACCHARIDOSIS, TYPE VI, SEVERE

ARSB, CYS117ARG
  
RCV000000926...

In a patient with severe mucopolysaccharidosis type VI (MPS6; 253200), Jin et al. (1992) identified a homozygous 349T-C transition in the ARSB gene, resulting in a cys117-to-arg (C117R) substitution. The patient's cultured fibroblasts showed about 2% of normal arylsulfatase B activity compared to a value of about 7% in cultured fibroblasts from a patient with mild MPS6 (L236P; 611542.0003).


.0003 MUCOPOLYSACCHARIDOSIS, TYPE VI, MILD

ARSB, LEU236PRO
  
RCV000000927...

In a patient with mild mucopolysaccharidosis type VI (MPS6; 253200), Jin et al. (1992) identified compound heterozygosity for 2 mutations in the ARSB gene: a 707T-C transition resulting in a leu236-to-pro (L236P) substitution, and a 1214G-A transition resulting in a cys405-to-tyr (C405Y; 611542.0004) substitution. The patient's cultured fibroblasts showed about 7% of normal arylsulfatase B activity compared to a value of about 2% in cultured fibroblasts from a patient with severe MPS6 (C117R; 611542.0002).


.0004 MUCOPOLYSACCHARIDOSIS, TYPE VI, SEVERE

ARSB, CYS405TYR
  
RCV000000928...

For discussion of the cys405-to-tyr (C405Y) mutation in the ARSB gene that was found in compound heterozygous state in a patient with mild mucopolysaccharidosis type VI (MPS6; 253200) by Jin et al. (1992), see 611542.0003.


.0005 MUCOPOLYSACCHARIDOSIS, TYPE VI, SEVERE

ARSB, 1-BP DEL, 238G
  
RCV000000929...

In an 11-year-old boy with severe mucopolysaccharidosis type VI (MPS6; 253200), Litjens et al. (1992) identified a homozygous 1-bp deletion (238delG), resulting in a frameshift and premature termination at codon 113. As an infant, he had coarse dysmorphic features, advanced bone age, dysostosis multiplex, and corneal clouding. Hydrocephalus required shunting at 4 years, and cervical cord compression resulting from upper cervical instability required surgical stabilization at 6 years of age.


.0006 MUCOPOLYSACCHARIDOSIS, TYPE VI, SEVERE

ARSB, 1-BP DEL, 743C
  
RCV000000930...

In a child with a severe form of Maroteaux-Lamy syndrome (MPS6; 253200), Isbrandt et al. (1996) identified compound heterozygosity for 2 deletions in the ARSB gene. One allele carried a 1-bp deletion (743delC) in exon 4 resulting in a frameshift and premature termination. The protein was predicted to be 221 amino acids, which is less than 42% of the 533 amino acid wildtype enzyme. The second allele carried an 11-bp deletion in exon 1 and a leu72-to-gln substitution (611542.0007). The patient presented at 2.5 years with facial dysmorphism, scoliosis and dysostosis multiplex, corneal clouding, hepatomegaly, and umbilical hernia. At age 7 years, he had short stature, severe kyphoscoliosis, restriction of joint movement, and pyramidal symptoms.


.0007 MUCOPOLYSACCHARIDOSIS, TYPE VI, SEVERE

ARSB, 11-BP DEL AND LEU72GLN
  
RCV000224599...

In a child with severe Maroteaux-Lamy syndrome (MPS6; 253200), Isbrandt et al. (1996) found a 1-bp deletion in the ARSB gene (611542.0006) and an 11-bp deletion which resulted in premature termination and a shortened protein predicted to be less than 23% of the length of the wildtype enzyme. In addition to the 11-bp deletion, they observed a 215T-A transversion resulting in a leu72-to-gln (L72Q) substitution on the same allele.


.0008 MUCOPOLYSACCHARIDOSIS, TYPE VI

ARSB, ARG95GLN
  
RCV000000932...

In a patient with a severe form of mucopolysaccharidosis type VI (MPS6; 253200), Litjens et al. (1996) identified compound heterozygosity for 2 mutations in the ARSB gene: a 284G-A transition resulting in an arg95-to-gln (R95Q) substitution, and H393P (611542.0010). She presented at age 13 months with mild developmental delay, thoracolumbar kyphosis, hepatosplenomegaly, and skeletal changes characteristic of the disorder. In another family, 2 sibs with a mild form of MPS6 were compound heterozygous for R95Q and Y210C (611542.0009). Functional expression studies in CHO cells showed that the R95Q mutant retained about 0.02% residual activity.


.0009 MUCOPOLYSACCHARIDOSIS, TYPE VI

ARSB, TYR210CYS
  
RCV000000933...

In 2 sibs with a mild form of mucopolysaccharidosis type VI (MPS6; 253200), Litjens et al. (1996) identified compound heterozygosity for 2 mutations in the ARSB gene: a 629A-G transition resulting in a tyr210-to-cys (Y210C) substitution, and R95Q (611542.0008). An additional unrelated patient with an intermediate phenotype was compound heterozygous for Y210C and H393P (611542.0010). Functional expression studies in CHO cells showed that the Y210C mutant retained about 2% residual activity.


.0010 MUCOPOLYSACCHARIDOSIS, TYPE VI

ARSB, HIS393PRO
  
RCV000000934...

In a patient with a severe form of mucopolysaccharidosis type VI (MPS6; 253200), Litjens et al. (1996) identified compound heterozygosity for 2 mutations in the ARSB gene: a 1178A-C transversion resulting in a his393-to-pro (H393P) substitution, and R95Q (611542.0008) Functional expression studies in CHO cells showed that the H393P mutant expressed no ARSB protein and thus had no residual activity.


.0011 MUCOPOLYSACCHARIDOSIS, TYPE VI

ARSB, IVS5AS, G-C,-1
  
RCV000000935

Garrido et al. (2007) identified a G-to-C transversion in intron 5 of the ARSB gene (1143-1G-C) in 21.9% of mutant alleles from 16 Spanish and Argentinian patients with mucopolysaccharidosis type VI (MPS6; 253200). RT-PCR analysis showed that the mutation resulted in the skipping of exon 6 and premature termination. Haplotype analysis indicated a founder effect.


.0012 MUCOPOLYSACCHARIDOSIS, TYPE VI

ARSB, IVS5AS, T-G, -8
  
RCV000000936

Garrido et al. (2007) identified a T-to-G transversion in intron 5 of the ARSB gene (1143-8T-G) in 12.5% of mutant alleles from 16 Spanish and Argentinian patients with mucopolysaccharidosis type VI (MPS6; 253200). RT-PCR analysis showed that the mutation resulted in the skipping of exon 6 and premature termination. Haplotype analysis indicated a founder effect.


REFERENCES

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  9. Fox, M. F., DuToit, D. L., Warnich, L., Retief, A. E. Regional localization of alpha-galactosidase (GLA) to Xpter-q22, hexosaminidase B (HEXB) to 5q13-qter, and arylsulfatase B (ARSB) to 5pter-q13. Cytogenet. Cell Genet. 38: 45-49, 1984. [PubMed: 6323102, related citations] [Full Text]

  10. Garrido, E., Chabas, A., Coll, M. J., Blanco, M., Dominguez, C., Grinberg, D., Vilageliu, L., Cormand, B. Identification of the molecular defects in Spanish and Argentinian mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) patients, including 9 novel mutations. Molec. Genet. Metab. 92: 122-130, 2007. [PubMed: 17643332, related citations] [Full Text]

  11. Haskins, M. E., Jezyk, P. F., Patterson, D. F. Mucopolysaccharide storage disease in three families of cats with arylsulfatase B deficiency: leukocyte studies and carrier identification. Pediat. Res. 13: 1203-1210, 1979. [PubMed: 229456, related citations] [Full Text]

  12. Hellkuhl, B., Grzeschik, K.-H. Assignment of a gene for arylsulfatase B to human chromosome 5 (EC 3.1.6.1) using human-mouse somatic cell hybrids. Cytogenet. Cell Genet. 22: 203-206, 1978. [PubMed: 752474, related citations] [Full Text]

  13. Isbrandt, D., Hopwood, J. J., von Figura, K., Peters, C. Two novel frameshift mutations causing premature stop codons in a patient with the severe form of Maroteaux-Lamy syndrome. Hum. Mutat. 7: 361-363, 1996. [PubMed: 8723688, related citations] [Full Text]

  14. Jezyk, P. F., Haskins, M. E., Patterson, D. F., Mellman, W. J., Greenstein, M. Mucopolysaccharidosis in a cat with arylsulfatase B deficiency: a model of Maroteaux-Lamy syndrome. Science 198: 834-836, 1977. [PubMed: 144321, related citations] [Full Text]

  15. Jin, W.-D., Jackson, C. E., Desnick, R. J., Schuchman, E. H. Mucopolysaccharidosis type VI: identification of three mutations in the arylsulfatase B gene of patients with the severe and mild phenotypes provides molecular evidence for genetic heterogeneity. Am. J. Hum. Genet. 50: 795-800, 1992. [PubMed: 1550123, related citations]

  16. Karageorgos, L., Brooks, D. A., Pollard, A., Melville, E. L., Hein, L. K., Clements, P. R., Ketteridge, D., Swiedler, S. J., Beck, M., Giugliani, R., Harmatz, P., Wraith, J. E., Guffon, N., Teles, E. L., Sa Miranda, M. C., Hopwood, J. J. Mutational analysis of 105 mucopolysaccharidosis type VI patients. Hum. Mutat. 28: 897-903, 2007. [PubMed: 17458871, related citations] [Full Text]

  17. Kunieda, T., Simonaro, C. M., Yoshida, M., Ikadai, H., Levan, G., Desnick, R. J., Schuchman, E. H. Mucopolysaccharidosis type VI in rats: isolation of cDNAs encoding arylsulfatase B, chromosomal localization of the gene, and identification of the mutation. Genomics 29: 582-587, 1995. [PubMed: 8575749, related citations] [Full Text]

  18. Litjens, T., Baker, E. G., Beckmann, K. R., Morris, C. P., Hopwood, J. J., Callen, D. F. Chromosomal localization of ARSB, the gene for human N-acetylgalactosamine-4-sulphatase. Hum. Genet. 82: 67-68, 1989. [PubMed: 2714781, related citations] [Full Text]

  19. Litjens, T., Brooks, D. A., Peters, C., Gibson, G. J., Hopwood, J. J. Identification, expression, and biochemical characterization of N-acetylgalactosamine-4-sulfatase mutations and relationship with clinical phenotype in MPS-VI patients. Am. J. Hum. Genet. 58: 1127-1134, 1996. [PubMed: 8651289, related citations]

  20. Litjens, T., Hopwood, J. J. Mucopolysaccharidosis type VI: structural and clinical implications of mutations in N-acetylgalactosamine-4-sulfatase. Hum. Mutat. 18: 282-295, 2001. [PubMed: 11668612, related citations] [Full Text]

  21. Litjens, T., Morris, C. P., Robertson, E. F., Peters, C., von Figura, K., Hopwood, J. J. An N-acetylgalactosamine-4-sulfatase mutation (delta-G-238) results in a severe Maroteaux-Lamy phenotype. Hum. Mutat. 1: 397-402, 1992. [PubMed: 1301949, related citations] [Full Text]

  22. McGovern, M. M., Mandell, N., Haskins, M., Desnick, R. J. Animal model studies of allelism: characterization of arylsulfatase B mutations in homoallelic and heteroallelic (genetic compound) homozygotes with feline mucopolysaccharidosis VI. Genetics 110: 733-749, 1985. [PubMed: 3928430, related citations] [Full Text]

  23. Schuchman, E. H., Jackson, C. E., Desnick, R. J. Human arylsulfatase B: MOPAC cloning, nucleotide sequence of a full-length cDNA, and regions of amino acid identity with arylsulfatases A and C. Genomics 6: 149-158, 1990. [PubMed: 1968043, related citations] [Full Text]

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Sonja A. Rasmussen - updated : 10/22/2020
Cassandra L. Kniffin - updated : 9/22/2009
Creation Date:
Cassandra L. Kniffin : 10/18/2007
carol : 11/04/2020
carol : 10/22/2020
carol : 10/11/2016
alopez : 10/06/2016
alopez : 04/30/2015
mcolton : 4/17/2015
mcolton : 2/12/2014
carol : 9/12/2013
wwang : 1/21/2011
wwang : 10/6/2009
ckniffin : 9/22/2009
carol : 10/31/2008
carol : 10/23/2007
ckniffin : 10/22/2007

* 611542

ARYLSULFATASE B; ARSB


HGNC Approved Gene Symbol: ARSB

SNOMEDCT: 52677002, 69463008;  


Cytogenetic location: 5q14.1     Genomic coordinates (GRCh38): 5:78,777,209-78,985,958 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
5q14.1 Mucopolysaccharidosis type VI (Maroteaux-Lamy) 253200 Autosomal recessive 3

TEXT

Description

The ARSB gene encodes arylsulfatase B (N-acetylgalactosamine 4-sulfatase; EC 3.1.6.12), a lysosomal enzyme that removes the C4 sulfate ester group from the N-acetylgalactosamine sugar residue at the nonreducing terminus of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin sulfate during lysosomal degradation (Karageorgos et al., 2007).


Cloning and Expression

Schuchman et al. (1990) cloned a full-length ARSB cDNA from a human testes cDNA library. The deduced 533-residue protein has 6 potential N-glycosylation sites. Comparison of the predicted amino acid sequences of arylsulfatases A (ARSA; 607574), B, and C (ARSC; 300747) demonstrated regions of identity, particularly in their N termini.

Kunieda et al. (1995) isolated the rat Arsb gene.


Gene Structure

The ARSB gene contains 8 exons and spans about 206 kb (Karageorgos et al., 2007).


Mapping

Hellkuhl and Grzeschik (1978) assigned a gene for arylsulfatase B to chromosome 5 by human-mouse somatic cell hybrids. By somatic cell hybridization methods, DeLuca et al. (1979) assigned arylsulfatases A and B to chromosomes 22 and 5, respectively. By study of an interstitial deletion of 5q12, Dudin et al. (1984) excluded ARSB and HEXB from this segment.

Fidzianska et al. (1984) assigned the ARSB locus to 5p11-qter by analysis of somatic cell hybrids isolated from 2 separate fusions of human fibroblasts carrying a translocation involving chromosome 5 with a Chinese hamster cell line. By study of rearranged chromosomes in human/hamster hybrids, using a tritium-labeled human genomic DNA fragment for in situ hybridization, Fidzianska et al. (1986) narrowed the assignment of ARSB to 5q11-q13.

Litjens et al. (1989) localized the ARSB gene to 5q13-q14.

By rat/mouse somatic cell hybridization, Kunieda et al. (1995) localized the rat Arsb gene to chromosome 2.


Molecular Genetics

In a patient with mucopolysaccharidosis type VI (253200), Wicker et al. (1991) identified a homozygous mutation in the ARSB gene (611542.0001).

In patients with MPS VI, Jin et al. (1992) identified homozygous or compound heterozygous mutations in the ARSB gene (611532.0002-611542.0004).

In 9 patients with MPS VI, Litjens et al. (1996) identified several mutations in the ARSB gene (see, e.g., 611542.0008-611542.0010). All patients were compound heterozygotes and showed variable phenotypes ranging from mild to severe. For each patient, the combined biochemical phenotypes of the 2 mutant sulfatase alleles demonstrated a good correspondence with the observed clinical phenotype.

Litjens and Hopwood (2001) stated that a total of 45 clinically relevant mutations had been identified in the ARSB gene in patients with mucopolysaccharidosis type VI. Missense mutations represented the largest group, with 31 identified. No common mutations had been described, making screening of the general population difficult.

Karageorgos et al. (2007) identified 83 different ARSB mutations among 105 patients with MPS VI. The most frequent mutation was Y210C (611542.0009), which was identified in 18% of patients and associated with an attenuated phenotype.

Among 12 Spanish and 4 Argentinian patients with MPS VI, Garrido et al. (2007) identified 19 different mutations, including 9 novel mutations, in the ARSB gene. The most common mutant alleles were splice site mutations, 611542.0011 and 611542.0012, which accounted for 21.9% and 12.5% of mutant alleles, respectively.

Tomanin et al. (2018) reviewed all variants in the ARSB gene in patients with MPS VI reported in the literature and in public databases and identified 908 alleles with 198 distinct nonpolymorphic variants from 478 patients. They also identified 3 benign variants that had previously been incorrectly reported as pathogenic. Most (59.5%) unique variants were missense, followed by small deletions (13.5%), nonsense (12.0%), splice site or intronic (5.0%), small duplications (3.0%), and large deletions (3.0%). Of the unique alleles, 31.7% appeared only once, with an additional 28.5% appearing twice. Of the identified patients, 54.8% were homozygous for pathogenic ARSB variants, 35.6% were heterozygous, 9.2% had only one allele reported, and 0.4% had both alleles unidentified. Pathogenic variants in ARSB did not appear to be concentrated in any particular region of the protein. Analysis of the genotype-phenotype correlation based on homozygotes was poorly informative for most variants, although some variants did appear to be associated with a more rapidly progressive phenotype. The authors emphasized the importance of submitting variants to public databases.


Animal Model

Yoshida et al. (1993) reported the clinical, morphologic, and biochemical features of a rat model of MPS VI. Affected rats had facial dysmorphia, dysostosis multiplex, and increased urinary excretion of glucosaminoglycans. Ultrastructural studies revealed storage of GAGs throughout the reticuloendothelial cells, cartilage, and other connective tissues, but no deposition was observed in the nervous system. Biochemical analyses demonstrated that the excreted GAG was dermatan sulfate and the activity of hepatic arylsulfatase B was less than 5% of the normal mean value. Pedigree analysis showed that the phenotype was inherited as an autosomal recessive single trait. Yoshida et al. (1994) demonstrated that the responsible gene lies on rat chromosome 2. It had been known that some loci on rat chromosome 2 correspond to those on human chromosome 5 and mouse chromosome 13. Kunieda et al. (1995) demonstrated furthermore MPS VI in rats was due to a homozygous 1-bp insertion (507insC) in the Arsb gene, resulting in a frameshift and premature termination at codon 258.

Evers et al. (1996) produced a targeted disruption of the Arsb gene in mice and found that homozygous mutant animals exhibited arylsulfatase B enzyme deficiency and elevated urinary secretion of dermatan sulfate. They developed progressive symptoms resembling those of MPS VI in humans. Around 4 weeks of age, facial dysmorphism became overt, long bones were shortened, and pelvic and costal abnormalities were observed. Major alterations in bone formation with perturbed cartilaginous tissues in newborns and widened, perturbed, and persisting growth plates in adult animals were seen. All major parenchymal organs showed storage of glycosaminoglycans preferentially in interstitial cells and macrophages. Affected mice were fertile and mortality was not elevated up to 15 months of age.

McGovern et al. (1985) studied the mutant arylsulfatase B enzymes in homozygotes for separately ascertained cat lines with MPS VI. They showed that the enzymes were distinguishable in physicokinetic and immunologic properties as well as in ability to dimerize with normal enzyme in heterozygotes.

Yogalingam et al. (1996) studied the Arsb (feline f4S) gene in MPS VI Siamese cats. They cloned the gene from a normal feline heart cDNA library, sequenced it, and identified a missense mutation (leu476pro; L476P) in the gene in MPS VI cats. Expression of the normal f4S gene, accompanied by mannose-6-phosphate (M6P), corrected the lysosomal storage of undegraded sulfated glycosaminoglycans in these cells. The observation suggested that expression of the normal f4S gene in MPS VI myoblasts is predominantly mediated by an M6P receptor (154540).

Crawley et al. (1996) used a feline model of MPS VI to investigate enzyme replacement therapy. They evaluated tissue distribution and clinical efficacy of 3 forms of recombinant human N-acetylgalactosamine-4-sulfatase. Intravenously administered enzyme was rapidly cleared from the circulation. The majority of the enzyme was distributed to the liver but was also detected in most other tissues. Tissue half-life was approximately 2-4 days. In 3 MPS VI cats, regular intravenous infusions of recombinant enzyme for up to 20 months showed variable reduction of storage vacuoles in Kupffer cells and connective tissues; however, cartilage chondrocytes remained vacuolated. Vertebral bone mineral volume was improved in 2 MPS VI cats in which therapy was initiated before skeletal maturity, and increased bone volume appeared to correlate with earlier age of onset of therapy. One cat showed greater mobility in response to therapy. Crawley et al. (1996) suggested that, given their results, significant reduction in disease progression and tissue pathology might be expected in patients with this disorder.

Crawley et al. (1997) reported a dose-related response effect of enzyme replacement therapy in MPS VI cats treated from birth. The evidence came from clinical, biochemical, and histopathologic observations.

Crawley et al. (1998) stated that the family of cats with MPS VI used for testing the efficacy of enzyme replacement therapy were homozygous for the L476P substitution in the Arsb gene. An additional mutation, asp520asn (D520N), inherited independently from L476P and identified in the same family of cats, resulted in 3 clinical phenotypes: L476P homozygotes exhibited dwarfism and facial dysmorphia due to epiphyseal dysplasia, abnormal low leukocyte 4S/beta-hexosaminidase ratios, dermatan sulfaturia, lysosomal inclusions in most tissues (including chondrocytes), corneal clouding, degenerative joint disease, and abnormal leukocyte inclusions. Similarly, D520N/D520N and L476P/D520N cats had abnormally low leukocyte 4S/beta-hexosaminidase ratios, mild dermatan sulfaturia, lysosomal inclusions in some chondrocytes, and abnormal leukocyte inclusions; however, both had normal growth and appearance. In addition, L476P/D520N cats had a high incidence of degenerative joint disease. Crawley et al. (1998) concluded that L476P/D520N cats have a very mild MPS VI phenotype not previously described in MPS VI humans. Yogalingam et al. (1998), from the same group, also reported biochemical and clinical assessment of L476P homozygous, D520N/L476P compound heterozygous, and D520N homozygous cats. They showed that the entire range of clinical phenotypes, from severe MPS VI, to mild MPS VI, to normal were clustered within a narrow range of residual 4S activity from 0.5 to 4.6% of normal levels. The results suggested that the D520N mutation causes a rapid degradation of 4S protein. The effect of this is partially ameliorated as a result of a significant elevation in the specific activity of mutant D520N 4S reaching the lysosomes.


ALLELIC VARIANTS 12 Selected Examples):

.0001   MUCOPOLYSACCHARIDOSIS, TYPE VI, INTERMEDIATE

ARSB, GLY137VAL
SNP: rs118203938, gnomAD: rs118203938, ClinVar: RCV000000925, RCV000677557

In a patient with mucopolysaccharidosis type VI (MPS6; 253200), born of consanguineous parents, Wicker et al. (1991) identified a homozygous 410G-T transversion in the ARSB gene, resulting in a gly137-to-val (G137V) substitution. The mutation did not affect protein synthesis, but severely reduced protein stability. The phenotype was of intermediate severity.


.0002   MUCOPOLYSACCHARIDOSIS, TYPE VI, SEVERE

ARSB, CYS117ARG
SNP: rs118203939, gnomAD: rs118203939, ClinVar: RCV000000926, RCV000677550

In a patient with severe mucopolysaccharidosis type VI (MPS6; 253200), Jin et al. (1992) identified a homozygous 349T-C transition in the ARSB gene, resulting in a cys117-to-arg (C117R) substitution. The patient's cultured fibroblasts showed about 2% of normal arylsulfatase B activity compared to a value of about 7% in cultured fibroblasts from a patient with mild MPS6 (L236P; 611542.0003).


.0003   MUCOPOLYSACCHARIDOSIS, TYPE VI, MILD

ARSB, LEU236PRO
SNP: rs118203940, ClinVar: RCV000000927, RCV000677586

In a patient with mild mucopolysaccharidosis type VI (MPS6; 253200), Jin et al. (1992) identified compound heterozygosity for 2 mutations in the ARSB gene: a 707T-C transition resulting in a leu236-to-pro (L236P) substitution, and a 1214G-A transition resulting in a cys405-to-tyr (C405Y; 611542.0004) substitution. The patient's cultured fibroblasts showed about 7% of normal arylsulfatase B activity compared to a value of about 2% in cultured fibroblasts from a patient with severe MPS6 (C117R; 611542.0002).


.0004   MUCOPOLYSACCHARIDOSIS, TYPE VI, SEVERE

ARSB, CYS405TYR
SNP: rs118203941, gnomAD: rs118203941, ClinVar: RCV000000928, RCV000179701, RCV000723435, RCV000779751

For discussion of the cys405-to-tyr (C405Y) mutation in the ARSB gene that was found in compound heterozygous state in a patient with mild mucopolysaccharidosis type VI (MPS6; 253200) by Jin et al. (1992), see 611542.0003.


.0005   MUCOPOLYSACCHARIDOSIS, TYPE VI, SEVERE

ARSB, 1-BP DEL, 238G
SNP: rs431905493, ClinVar: RCV000000929, RCV000677521

In an 11-year-old boy with severe mucopolysaccharidosis type VI (MPS6; 253200), Litjens et al. (1992) identified a homozygous 1-bp deletion (238delG), resulting in a frameshift and premature termination at codon 113. As an infant, he had coarse dysmorphic features, advanced bone age, dysostosis multiplex, and corneal clouding. Hydrocephalus required shunting at 4 years, and cervical cord compression resulting from upper cervical instability required surgical stabilization at 6 years of age.


.0006   MUCOPOLYSACCHARIDOSIS, TYPE VI, SEVERE

ARSB, 1-BP DEL, 743C
SNP: rs431905494, ClinVar: RCV000000930, RCV000677591

In a child with a severe form of Maroteaux-Lamy syndrome (MPS6; 253200), Isbrandt et al. (1996) identified compound heterozygosity for 2 deletions in the ARSB gene. One allele carried a 1-bp deletion (743delC) in exon 4 resulting in a frameshift and premature termination. The protein was predicted to be 221 amino acids, which is less than 42% of the 533 amino acid wildtype enzyme. The second allele carried an 11-bp deletion in exon 1 and a leu72-to-gln substitution (611542.0007). The patient presented at 2.5 years with facial dysmorphism, scoliosis and dysostosis multiplex, corneal clouding, hepatomegaly, and umbilical hernia. At age 7 years, he had short stature, severe kyphoscoliosis, restriction of joint movement, and pyramidal symptoms.


.0007   MUCOPOLYSACCHARIDOSIS, TYPE VI, SEVERE

ARSB, 11-BP DEL AND LEU72GLN
SNP: rs1561197425, rs397514441, gnomAD: rs397514441, ClinVar: RCV000224599, RCV000677514, RCV000779749, RCV000779750, RCV003338374

In a child with severe Maroteaux-Lamy syndrome (MPS6; 253200), Isbrandt et al. (1996) found a 1-bp deletion in the ARSB gene (611542.0006) and an 11-bp deletion which resulted in premature termination and a shortened protein predicted to be less than 23% of the length of the wildtype enzyme. In addition to the 11-bp deletion, they observed a 215T-A transversion resulting in a leu72-to-gln (L72Q) substitution on the same allele.


.0008   MUCOPOLYSACCHARIDOSIS, TYPE VI

ARSB, ARG95GLN
SNP: rs118203942, gnomAD: rs118203942, ClinVar: RCV000000932, RCV000078002

In a patient with a severe form of mucopolysaccharidosis type VI (MPS6; 253200), Litjens et al. (1996) identified compound heterozygosity for 2 mutations in the ARSB gene: a 284G-A transition resulting in an arg95-to-gln (R95Q) substitution, and H393P (611542.0010). She presented at age 13 months with mild developmental delay, thoracolumbar kyphosis, hepatosplenomegaly, and skeletal changes characteristic of the disorder. In another family, 2 sibs with a mild form of MPS6 were compound heterozygous for R95Q and Y210C (611542.0009). Functional expression studies in CHO cells showed that the R95Q mutant retained about 0.02% residual activity.


.0009   MUCOPOLYSACCHARIDOSIS, TYPE VI

ARSB, TYR210CYS
SNP: rs118203943, gnomAD: rs118203943, ClinVar: RCV000000933, RCV000078003, RCV000779747, RCV003904792

In 2 sibs with a mild form of mucopolysaccharidosis type VI (MPS6; 253200), Litjens et al. (1996) identified compound heterozygosity for 2 mutations in the ARSB gene: a 629A-G transition resulting in a tyr210-to-cys (Y210C) substitution, and R95Q (611542.0008). An additional unrelated patient with an intermediate phenotype was compound heterozygous for Y210C and H393P (611542.0010). Functional expression studies in CHO cells showed that the Y210C mutant retained about 2% residual activity.


.0010   MUCOPOLYSACCHARIDOSIS, TYPE VI

ARSB, HIS393PRO
SNP: rs118203944, gnomAD: rs118203944, ClinVar: RCV000000934, RCV000424623

In a patient with a severe form of mucopolysaccharidosis type VI (MPS6; 253200), Litjens et al. (1996) identified compound heterozygosity for 2 mutations in the ARSB gene: a 1178A-C transversion resulting in a his393-to-pro (H393P) substitution, and R95Q (611542.0008) Functional expression studies in CHO cells showed that the H393P mutant expressed no ARSB protein and thus had no residual activity.


.0011   MUCOPOLYSACCHARIDOSIS, TYPE VI

ARSB, IVS5AS, G-C,-1
SNP: rs431905495, gnomAD: rs431905495, ClinVar: RCV000000935

Garrido et al. (2007) identified a G-to-C transversion in intron 5 of the ARSB gene (1143-1G-C) in 21.9% of mutant alleles from 16 Spanish and Argentinian patients with mucopolysaccharidosis type VI (MPS6; 253200). RT-PCR analysis showed that the mutation resulted in the skipping of exon 6 and premature termination. Haplotype analysis indicated a founder effect.


.0012   MUCOPOLYSACCHARIDOSIS, TYPE VI

ARSB, IVS5AS, T-G, -8
SNP: rs431905496, gnomAD: rs431905496, ClinVar: RCV000000936

Garrido et al. (2007) identified a T-to-G transversion in intron 5 of the ARSB gene (1143-8T-G) in 12.5% of mutant alleles from 16 Spanish and Argentinian patients with mucopolysaccharidosis type VI (MPS6; 253200). RT-PCR analysis showed that the mutation resulted in the skipping of exon 6 and premature termination. Haplotype analysis indicated a founder effect.


See Also:

Fox et al. (1984); Haskins et al. (1979); Jezyk et al. (1977); Villani et al. (1999); Vine et al. (1981); Weller and Austen (1983)

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Contributors:
Sonja A. Rasmussen - updated : 10/22/2020
Cassandra L. Kniffin - updated : 9/22/2009

Creation Date:
Cassandra L. Kniffin : 10/18/2007

Edit History:
carol : 11/04/2020
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carol : 10/11/2016
alopez : 10/06/2016
alopez : 04/30/2015
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mcolton : 2/12/2014
carol : 9/12/2013
wwang : 1/21/2011
wwang : 10/6/2009
ckniffin : 9/22/2009
carol : 10/31/2008
carol : 10/23/2007
ckniffin : 10/22/2007