GUSB

protein-coding

glucuronidase beta, the group of Glycoside hydrolases

Gene summary

This gene encodes a hydrolase that degrades glycosaminoglycans, including heparan sulfate, dermatan sulfate, and chondroitin-4,6-sulfate. The enzyme forms a homotetramer that is localized to the lysosome. Mutations in this gene result in mucopolysaccharidosis type VII. Alternative splicing results in multiple transcript variants. There are many pseudogenes of this locus in the human genome.[provided by RefSeq, May 2014]

MANE transcript

NM_000181.4

Inheritance

ClinVar variants

P:126U:200B:260

Top phenotype

Mucopolysaccharidosis type VII

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr7:65,960,684-65,982,215

External References & Databases

Ensembl (ENSG00000169919)

Transcript & Mutation Effects

hg38 • Region Span ~21.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mucopolysaccharidosis type 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009662

Submitter: ClinGen

The relationship between the GUSB gene and mucopolysaccharidosis type 7 (MPS7), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of June 27, 2022. GUSB encodes beta-glucuronidase, a lysosomal enzyme that catalyzes the hydrolysis of beta-D-glucuronic acid residues in the degradation of glycosaminoglycans (GAGs), including the degradation of heparan sulfate, dermatan sulfate, and chondroitin-4,6-sulfate (PMID: 3468507). Among individuals with MPS7, beta-glucuronidase deficiency results in accumulation of these GAGs in the lysosomes of multiple tissues, resulting in the characteristic disease manifestations of MPS7, which include neurologic impairment, hepatosplenomegaly, and skeletal dysplasia (as reviewed in PMID: 26908836). In addition to skeletal dysplasia, cases can present with fetal hydrops and reduced β-glucuronidase activity prenatally (PMID 8644704, 8111413, 811412). The disease mechanism of MPS7 is loss of function. MPS7 was first reported in 1973 (PMID: 4265197) and the first report of biallelic variants in GUSB among patients with MPS7 was published in 1900 (PMID: 2115490). Both case-level (genetic) and experimental evidence support the relationship between MPS7 and GUSB. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants, as well as larger intragenic deletions (PMID: 19224584). In total, 11 variants from seven probands in six publications were curated, including the prevalent missense variants c.526C>T (p.L176F), c.1856C>T (p.A619V), and c.1144C>T (p.R382C), which are estimated to respectively account for 20.4%, 4.9%, and 3.9% 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 GUSB and MPS7 includes the biochemical function of the gene product (the beta-glucuronidase enzyme) being consistent with the clinical and biochemical findings identified individuals with MPS7 (PMID: 4265197, PMID: 26908836), the biochemical and clinical features of a GUSB knockout mouse animal (PMID: 2495302, PMID: 8101990), and the impact of enzyme replacement therapy among human MPS7 patients (PMID: 32063397). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, GUSB is definitively associated with MPS7. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases GCEP on July 5, 2022 (SOP v9). Additional information, regarding the prenatal presentation of MPS7, was added by the Prenatal GCEP on Jan 3, 2025.

mucopolysaccharidosis type 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009662

Submitter: Labcorp Genetics (formerly Invitae)

mucopolysaccharidosis type 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009662

Submitter: Genomics England PanelApp

mucopolysaccharidosis type 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009662

Submitter: PanelApp Australia

mucopolysaccharidosis type 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009662

Submitter: G2P

mucopolysaccharidosis type 7SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009662

Submitter: Orphanet

Clinical Genomic Database (CGD)

Mucopolysaccharidosis type VIIAR

Manifestation: Biochemical; Cardiovascular; Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: Enzyme replacement therapy is available, and has been approved for both pediatric and adult patients; BMT has been described

Comments: The condition can include cardiac manifestations

Refs: 4265197; 144057; 101485; 6813001; 1702266; 7680524; 9099834; 9543069; 12403825; 12522561; 12748853; 19224584; 26908836; 28595941; 29478819

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GUSB variants in ClinVar

10 Conditions Cataloged

Mucopolysaccharidosis type 7Total: 645

not specifiedTotal: 86

not providedTotal: 69

Inborn genetic diseasesTotal: 69

GUSB-related disorderTotal: 48

Non-immune hydrops fetalisTotal: 5

GUSB-related disordersTotal: 5

Mucopolysaccharidosis type 6Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000181.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	2 clinvar	243 clinvar	2 clinvar	248
missense	5 clinvar	40 clinvar	189 clinvar	14 clinvar		248
nonsense	16 clinvar	12 clinvar	1 clinvar			29
start loss	1 clinvar	1 clinvar				2
frameshift	26 clinvar	10 clinvar	3 clinvar	1 clinvar		40
splice donor/acceptor (+/-2bp)	1 clinvar	13 clinvar	5 clinvar			19
Total	49	77	200	258	2	586

Highest pathogenic variant AF is 0.00007251587

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 194 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000181.4	RefSeq	NP_000172.2	12	MANE Select
ENST00000304895.9	Ensembl	ENSP00000302728.4	12	MANE Select
NM_001284290.2	RefSeq	NP_001271219.1	10	Standard
NM_001293104.2	RefSeq	NP_001280033.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Drug metabolism - other enzymes - Homo sapiens (human)
Porphyrin and chlorophyll metabolism - Homo sapiens (human)
Pentose and glucuronate interconversions - Homo sapiens (human)
Glycosaminoglycan degradation - Homo sapiens (human)

Biological Process

carbohydrate metabolic process
glycosaminoglycan catabolic process
glucuronoside catabolic process
hyaluronan catabolic process
neutrophil degranulation

Molecular Function

beta-glucuronidase activity
signaling receptor binding
protein domain specific binding
carbohydrate binding

Cellular Component

extracellular region
extracellular space
membrane
azurophil granule lumen
lysosomal lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304895
Coding exons: 12
Length: 21631
Individuals with no LoFs: 125648
Homozygous LoFs: 0
Heterozygous LoFs: 100
Defined: 125748
p: 0.000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.10	315	375	0.840	0.0000239	4208
Missense (PolyPhen)		104	153.55	0.67732		1771
Synonymous	-0.798	173	160	1.08	0.0000110	1282
Loss of Function	2.71	18	35.4	0.508	0.00000202	358

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00058	0.00055	rare
Latino/Admixed American	0.00050	0.00049	rare
Ashkenazi Jewish	0.00033	0.00030	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00020	0.00018	rare
European (Non-Finnish)	0.00048	0.00043	rare
South Asian	0.00045	0.00042	rare
Other	0.00057	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in the degradation of dermatan and keratan sulfates.;
Disease: DISEASE: Mucopolysaccharidosis 7 (MPS7) [MIM:253220]: An autosomal recessive lysosomal storage disease characterized by inability to degrade glucuronic acid-containing glycosaminoglycans. The phenotype is highly variable, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment. {ECO:0000269|PubMed:12522561, ECO:0000269|PubMed:12859417, ECO:0000269|PubMed:1702266, ECO:0000269|PubMed:7573038, ECO:0000269|PubMed:7633414, ECO:0000269|PubMed:7680524, ECO:0000269|PubMed:8089138, ECO:0000269|PubMed:8111412, ECO:0000269|PubMed:8111413, ECO:0000269|PubMed:8644704, ECO:0000269|PubMed:8707294, ECO:0000269|PubMed:9099834, ECO:0000269|PubMed:9490302}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.0891
RVIS EVS: -0.82
RVIS percentile EVS: 11.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.996

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium