ARSB
protein-codingarylsulfatase B, the group of Sulfatases
Gene summary
Arylsulfatase B encoded by this gene belongs to the sulfatase family. The arylsulfatase B homodimer hydrolyzes sulfate groups of N-Acetyl-D-galactosamine, chondriotin sulfate, and dermatan sulfate. The protein is targeted to the lysozyme. Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Dec 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~208.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009661
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009661
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009661
Submitter: ClinGen
The relationship between the ARSB gene and mucopolysaccharidosis type 6 (MPS6), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 9, 2022. ARSB encodes aryl sulfatase B (ASB), an enzyme that catalyzes the removal of the C4 sulfate ester group from the N-acetylgalactosamine sugar residue at the nonreducing terminus of the glycosaminoglycans (GAGs) dermatan sulfate (DS) and chondroitin sulfate (CS) during lysosomal degradation (as reviewed in PMID: 17458871; PMID: 30118150). Among individuals with MPS6, ASB deficiency results in accumulation of DS and CS, which leads to symptoms including short stature, coarse facies, dysostosis multiplex, hepatosplenomegaly, corneal clouding, and cardiac disease. The disease mechanism of MPS6 is loss of function. MPS6 was first reported in 1963 (PMID: 14091597) and the first report of biallelic variants in ARSB among patients with MPS6 was published in 1991 (PMID: 1718978). Since then, at least 201 unique variants in 478 cases have been identified (PMID: 30118150). Both case-level (genetic) and experimental evidence support the relationship between MPS6 and ARSB. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants, as well as larger deletions and duplications. In total, fourteen variants from nine probands in six publications were curated. Of note, three missense variants, c.454C>T (p.Arg152Trp), c.962T>C (p.Leu321Pro), and c.629A>G (p.Tyr210Cys), are estimated to account for 18.5% of reported cases. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between ARSB and MPS6 includes the biochemical function of the gene product (the ASB enzyme) being consistent with the clinical and biochemical findings identified individuals with MPS6 (PMID: 20385007; PMID: 4271367), the biochemical and clinical features of a feline animal model homozygous for the p.Leu476Pro variant (PMID: 8910299), and the impact of enzyme replacement therapy among human MPS6 patients (PMID: 16647419). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, ARSB is definitively associated with MPS6. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0009661
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009661
Submitter: Illumina
Inheritance Pattern: AR
Disease ID:MONDO:0009661
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009661
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Ophthalmologic
Intervention: Biochemical; Cardiovascular
Rationale: Enzyme replacement therapy is available; The condition can include cardiovascular manifestations, and awareness may allow surveillance and early detection, which may lead to improved management; BMT has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ARSB variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000046.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 11 | 237 | 6 | 254 | ||
| missense | 13 | 117 | 214 | 12 | 356 | |
| nonsense | 24 | 25 | 1 | 1 | 51 | |
| start loss | 0 | |||||
| frameshift | 33 | 49 | 82 | |||
| splice donor/acceptor (+/-2bp) | 8 | 19 | 27 | |||
| Total | 78 | 210 | 226 | 250 | 6 | 770 |
Highest pathogenic variant AF is 0.00022057795
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000037.2 | 8 | MANE Select | |
| Ensembl | ENSP00000264914.4 | 8 | MANE Select | |
| RefSeq | NP_942002.1 | 7 | Standard | |
| Ensembl | ENSP00000379455.3 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Lysosome - Homo sapiens (human)
- Glycosaminoglycan degradation - Homo sapiens (human)
- Neutrophil degranulation
- Metabolism of carbohydrates
- Metabolism of lipids
Biological Process
- autophagy
- lysosome organization
- lysosomal transport
- central nervous system development
- response to nutrient
Molecular Function
- N-acetylgalactosamine-4-sulfatase activity
- arylsulfatase activity
- metal ion binding
Cellular Component
- extracellular region
- mitochondrion
- lysosome
- endoplasmic reticulum lumen
- rough endoplasmic reticulum
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000264914
- Coding exons
- 8
- Length
- 208879
- Individuals with no LoFs
- 125709
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 39
- Defined
- 125748
- p
- 0.000155
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.631 | 254 | 284 | 0.895 | 0.0000159 | 3412 |
| Missense (PolyPhen) | 95 | 124.55 | 0.76272 | 1514 | ||
| Synonymous | 0.521 | 108 | 115 | 0.938 | 0.00000634 | 1105 |
| Loss of Function | 1.33 | 16 | 22.9 | 0.699 | 0.00000134 | 259 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.00018 | 0.00018 | rare |
| European (Non-Finnish) | 0.00021 | 0.00021 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Removes sulfate groups from chondroitin-4-sulfate (C4S) and regulates its degradation (PubMed:19306108). Involved in the regulation of cell adhesion, cell migration and invasion in colonic epithelium (PubMed:19306108). In the central nervous system, is a regulator of neurite outgrowth and neuronal plasticity, acting through the control of sulfate glycosaminoglycans and neurocan levels (By similarity). {ECO:0000250|UniProtKB:P50430, ECO:0000269|PubMed:19306108}.;
- Disease
- DISEASE: Mucopolysaccharidosis 6 (MPS6) [MIM:253200]: An autosomal recessive lysosomal storage disease characterized by intracellular accumulation of dermatan sulfate. Clinical features can include abnormal growth, short stature, stiff joints, skeletal malformations, corneal clouding, hepatosplenomegaly, and cardiac abnormalities. A wide variation in clinical severity is observed. {ECO:0000269|PubMed:10036316, ECO:0000269|PubMed:10738004, ECO:0000269|PubMed:11802522, ECO:0000269|PubMed:14974081, ECO:0000269|PubMed:1550123, ECO:0000269|PubMed:1718978, ECO:0000269|PubMed:19259130, ECO:0000269|PubMed:8116615, ECO:0000269|PubMed:8125475, ECO:0000269|PubMed:8541342, ECO:0000269|PubMed:8651289}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple sulfatase deficiency (MSD) [MIM:272200]: A clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post- translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay. {ECO:0000269|PubMed:15146462}. Note=The protein represented in this entry is involved in disease pathogenesis. Arylsulfatase B activity is impaired in multiple sulfatase deficiency due to mutations in SUMF1. SUMF1 mutations result in defective post-translational modification of ARSB at residue Cys-91 that is not converted to 3-oxoalanine.;
Recessive Scores
- pRec
- 0.256
Intolerance Scores
- LoFtool
- 0.0956
- RVIS EVS
- 0.02
- RVIS percentile EVS
- 55.61
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.835
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | Medium | Medium |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |