GeneBe

GNS

protein-coding

glucosamine (N-acetyl)-6-sulfatase, the group of Sulfatases

Gene summary

The product of this gene is a lysosomal enzyme found in all cells. It is involved in the catabolism of heparin, heparan sulphate, and keratan sulphate. Deficiency of this enzyme results in the accumulation of undegraded substrate and the lysosomal storage disorder mucopolysaccharidosis type IIID (Sanfilippo D syndrome). Mucopolysaccharidosis type IIID is the least common of the four subtypes of Sanfilippo syndrome. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002076.4

Inheritance

AR

ClinVar variants

P:84U:217B:262

Top phenotype

Mucopolysaccharidosis IIID (Sanfilippo syndrome D)

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr12:64,713,445-64,759,431

External References & Databases

Ensembl (ENSG00000135677)NCBI Gene (2799)OMIM (607664)HGNC:4422GenCCUniProt (P15586)AlphaFoldClinVar (GNS)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~46.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mucopolysaccharidosis type 3DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009658

Submitter: Labcorp Genetics (formerly Invitae)

mucopolysaccharidosis type 3DDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009658

Submitter: G2P

mucopolysaccharidosis type 3DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009658

Submitter: Genomics England PanelApp

mucopolysaccharidosis type 3DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009658

Submitter: PanelApp Australia

mucopolysaccharidosis type 3DDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009658

Submitter: Natera

mucopolysaccharidosis type 3DSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009658

Submitter: Orphanet

mucopolysaccharidosis type 3DDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009658

Submitter: ClinGen

The relationship between the GNS gene and mucopolysaccharidosis type IIID (MPS3D), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 2, 2022. GNS encodes N-acetylglucosamine-6-sulfatase (PMID: 3391615), an enzyme that is involved in the glycosaminoglycan degradation via catalyzing the hydrolysis of the 6-sulfate groups of the N-acetyl-D-glucosamine 6-sulfate moieties of heparan sulfate and keratan sulfate (PMID: 3689315). Individuals with MPS3D show impaired N-acetylglucosamine-6-sulfate sulfatase activity, resulting in lysosomal accumulation of glycosaminoglycans in multiple tissues, which leads to characteristic disease manifestations including CNS degeneration and skeletal dysostosis (PMID: 18392742). The disease mechanism of MPS3D is loss of function. MPS3D was first reported in 1980 by Kresse et al. (PMID: 6450420) and the first reports of biallelic variants in GNS among MPS3D cases in 2003 by Mok et al. (PMID: 12573255) and Beasley et al. (PMID: 12624138). Both case-level (genetic) and experimental evidence support the relationship between GNS and MPS3D. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 12573255, PMID: 12624138, PMID: 17998446, PMID: 17998446, PMID: 19650410, PMID: 16990043, PMID: 16990043, PMID: 20232353). In total, eight variants from eight probands in eight publications were curated. 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 GNS and MPS3D includes: the biochemical function of the gene product (N-acetylglucosamine-6-sulfatase) being consistent with the clinical and biochemical findings identified individuals with MPS3D (PMID: 18392742); the biochemical and clinical features of GNS knockout mice (PMID: 28334745); and rescue of enzyme function via gene therapy in GNS knockout mice (PMID: 28334745). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, GNS is definitively associated with MPS3D. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 2, 2022 (SOP v9).

Clinical Genomic Database (CGD)

Mucopolysaccharidosis IIID (Sanfilippo syndrome D)AR

Manifestation: Biochemical; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 6450420; 12624138; 12573255; 17998446; 19650410; 20232353Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GNS variants in ClinVar

6 Conditions Cataloged
Mucopolysaccharidosis, MPS-III-DTotal: 686
Sanfilippo syndromeTotal: 71
Inborn genetic diseasesTotal: 63
not providedTotal: 53
GNS-related disorderTotal: 23
not specifiedTotal: 22

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002076.4. 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.

EffectPLPVUSLBBSum
synonymous
11
clinvar
247
clinvar
3
clinvar
 261
missense
1
clinvar
198
clinvar
12
clinvar
 211
nonsense
18
clinvar
8
clinvar
2
clinvar
 28
start loss
0
frameshift
28
clinvar
12
clinvar
1
clinvar
 41
splice donor/acceptor (+/-2bp)
6
clinvar
11
clinvar
5
clinvar
 22
Total52322172593563

Highest pathogenic variant AF is 0.000013183668

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002076.4RefSeqNP_002067.114MANE Select
ENST00000258145.8EnsemblENSP00000258145.314MANE Select
ENST00000418919.6EnsemblENSP00000413130.213Standard
ENST00000418919.7EnsemblENSP00000413130.213Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)
  • Glycosaminoglycan degradation - Homo sapiens (human)
  • Lysosome Vesicle Biogenesis
  • Clathrin derived vesicle budding
  • Neutrophil degranulation

Biological Process

  • glycosaminoglycan catabolic process
  • keratan sulfate catabolic process
  • neutrophil degranulation

Molecular Function

  • protein binding
  • glycosaminoglycan binding
  • N-acetylglucosamine-6-sulfatase activity
  • sulfuric ester hydrolase activity
  • metal ion binding

Cellular Component

  • extracellular region
  • lysosome
  • azurophil granule lumen
  • lysosomal lumen
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000258145
Coding exons
14
Length
46003
Individuals with no LoFs
125726
Homozygous LoFs
0
Heterozygous LoFs
22
Defined
125748
p
0.0000875
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.372343010.7770.00001553613
Missense (PolyPhen)51102.580.497181326
Synonymous0.3281091130.9610.000005891065
Loss of Function3.221130.10.3660.00000144356

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000130.00012rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.000120.00012rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease
DISEASE: Mucopolysaccharidosis 3D (MPS3D) [MIM:252940]: A form of mucopolysaccharidosis type 3, an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate. MPS3 is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life. {ECO:0000269|PubMed:12573255, ECO:0000269|PubMed:20232353}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.325

Intolerance Scores

LoFtool
0.262
RVIS EVS
-0.31
RVIS percentile EVS
31.93

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.726

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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