IDUA

protein-coding

alpha-L-iduronidase, the group of Glycoside hydrolases

Gene summary

This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]

MANE transcript

NM_000203.5

Inheritance

ClinVar variants

P:482U:518B:554

Top phenotype

Mucopolysaccharidosis type I (Mucopolysaccharidosis Ih; Mucopolysaccharidosis Is; Mucopolysaccharidosis Ih/s)

gnomAD constraint

pLI —, LoF o/e 0.82

Max pathogenic AF

—

Genomic locus

chr4:986,997-1,004,564

External References & Databases

Ensembl (ENSG00000127415)

Transcript & Mutation Effects

hg38 • Region Span ~17.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Hurler syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011758

Submitter: Genomics England PanelApp

Hurler-Scheie syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011759

Submitter: Genomics England PanelApp

mucopolysaccharidosis type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0001586

Submitter: Myriad Women's Health

Hurler-Scheie syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011759

Submitter: Orphanet

Scheie syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011760

Submitter: Orphanet

Scheie syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011760

Submitter: Labcorp Genetics (formerly Invitae)

mucopolysaccharidosis type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0001586

Submitter: Natera

Hurler syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011758

Submitter: Orphanet

mucopolysaccharidosis type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0001586

Submitter: PanelApp Australia

mucopolysaccharidosis type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0001586

Submitter: ClinGen

The relationship between IDUA and mucopolysaccharidosis type 1 (MPS 1), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 30, 2020. IDUA encodes alpha-L-iduronidase, a lysosomal hydrolase involved in the degradation of the sulfated glycosaminoglycans (GAGs), dermatan sulfate and heparan sulfate. Deficiency of alpha-L-iduronidase results in the lysosomal accumulation of dermatan sulfate and heparan sulfate. The resulting clinical phenotype, MPS 1, is a progressive multisystem disease. Historically, patients have been categorized as either Hurler (early onset, most severe), Scheie (later onset, least severe), or Hurler-Scheie (intermediate) phenotypes. However, the MPS 1 has a clinically continuous spectrum from severe to mild and, more recently, patients have been described as either “severe” or “attenuated” MPS 1 (see GeneReviews, Clarke, 2016, https://www.ncbi.nlm.nih.gov/books/NBK1162/). Children with severe MPS1 may have nonspecific symptoms, such as umbilical or inguinal hernia, or frequent upper respiratory-tract infections in the first year of life. These children develop coarse of the facial features, gibbus deformity of the lower spine, progressive skeletal dysplasia (dysostosis multiplex), and decreased linear growth, as well as progressive and profound intellectual disability, and hearing loss. Death, usually caused by cardiorespiratory failure, typically occurs by age 10 years. The severity and rate of disease progression ranges in individuals with attenuated MPS1 from serious life-threatening complications leading to death in the second to third decades to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. Learning difficulties are present in some individuals (from GeneReviews, Clarke, 2016, https://www.ncbi.nlm.nih.gov/books/NBK1162/). Variants in IDUA were first reported in humans with MPS 1 in 1992 (Scott et al, PMID 1301196). Since then, over 200 variants in IDUA have been reported (PMID 29393969). The most commonly reported variants are p.Gln70Ter and p.Trp402Ter (PMID 29393969). The mechanism of disease is loss of function. Evidence supporting this gene-disease relationship includes case-level and experimental data. Thirteen variants in twelve probands from six publications were curated (Scott et al, 1992, PMID 1301196; Yamagishi et al, 1996, PMID 8664897; Vazna et al, 2009, PMID 19396826; Chkioua et al, 2011, PMID 22074387; Bertola et al, 2011, PMID 21394825; Ngiwsara et al, 2018, PMID 29282708) and included frameshift, nonsense, splice site, missense, and stop loss variants. More information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the function of alpha-L-iduronidase, which is consistent with the accumulation of GAGs observed in patients (Dorfman et al, 1976, PMID 813230), functional studies in fibroblasts from patients with MPS 1 (Ashton et al, 1992, PMID 1550122), the biochemical and clinical features of a mouse model with a variant analogous to a human IDUA variant causing MPS1 (Wang et al, 2010, PMID 19751987), and the impact of enzyme replacement therapy with recombinant alpha-L-iduronidase, on clinical phenotype (Clarke et al, 2009, PMID 19117887). More information is available in the literature but the maximum score for experimental evidence (6 points) has been reached. In summary, IDUA is definitively associated with MPS 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity assessment includes data curated by Myriad Women’s Health.

Scheie syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011760

Submitter: G2P

Scheie syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011760

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Mucopolysaccharidosis type I (Mucopolysaccharidosis Ih; Mucopolysaccharidosis Is; Mucopolysaccharidosis Ih/s)AR

Manifestation: Biochemical; Cardiovascular; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic; Pulmonary

Intervention: Biochemical

Rationale: Enzyme replacement therapy, the timing of which affects outcome is available, but may not affect cerebral manifestations; HSCT and umbilical cord blood transplantation has been described as beneficial

Comments: The conditions includes a wide degree of severity, and multiple subtypes, including Scheie syndrome, Hurler-Scheie syndrome, and Hurler syndrome

Refs: 6139633; 9516162; 7550242; 11735025; 11172140; 15128896; 19748810; 20301341; 21502868; 25103575; 28595941; 31127942

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IDUA variants in ClinVar

28 Conditions Cataloged

Mucopolysaccharidosis type 1Total: 1627

not providedTotal: 805

Inborn genetic diseasesTotal: 366

Hurler syndromeTotal: 272

Nephrolithiasis susceptibility caused by SLC26A1Total: 182

HypersulfaturiaTotal: 180

not specifiedTotal: 150

Mucopolysaccharidosis, MPS-I-H/STotal: 130

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000203.5. 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			23 clinvar	518 clinvar	1 clinvar	542
missense	23 clinvar	105 clinvar	486 clinvar	32 clinvar	3 clinvar	649
nonsense	45 clinvar	34 clinvar	3 clinvar			82
start loss	6 clinvar					6
frameshift	115 clinvar	75 clinvar	4 clinvar			194
splice donor/acceptor (+/-2bp)	31 clinvar	48 clinvar	2 clinvar			81
Total	220	262	518	550	4	1554

Highest pathogenic variant AF is 0.0012653201

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000203.5	RefSeq	NP_000194.2	14	MANE Select
ENST00000514224.2	Ensembl	ENSP00000425081.2	14	MANE Select
NM_001363576.1	RefSeq	NP_001350505.1	11	Standard
ENST00000247933.10	Ensembl	ENSP00000247933.4	14	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)
Metabolism of carbohydrates
HS-GAG degradation
Heparan sulfate/heparin (HS-GAG) metabolism

Biological Process

disaccharide metabolic process
glycosaminoglycan catabolic process
chondroitin sulfate catabolic process
dermatan sulfate catabolic process
heparin catabolic process

Molecular Function

L-iduronidase activity
signaling receptor binding

Cellular Component

coated vesicle
lysosomal lumen
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000247933
Coding exons: 14
Length: 17532
Individuals with no LoFs: 125525
Homozygous LoFs: 0
Heterozygous LoFs: 153
Defined: 125678
p: 0.000609

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.598	373	342	1.09	0.0000191	4038
Missense (PolyPhen)		151	145.32	1.0391		1738
Synonymous	-2.69	205	162	1.27	0.0000102	1379
Loss of Function	0.882	22	26.9	0.817	0.00000120	298

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00034	0.00033	rare
Finnish	0.0018	0.0018	notable
European (Non-Finnish)	0.00092	0.00088	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Mucopolysaccharidosis 1H (MPS1H) [MIM:607014]: A severe form of mucopolysaccharidosis type 1, a rare lysosomal storage disease characterized by progressive physical deterioration with urinary excretion of dermatan sulfate and heparan sulfate. Patients with MPS1H usually present, within the first year of life, a combination of hepatosplenomegaly, skeletal deformities, corneal clouding and severe mental retardation. Obstructive airways disease, respiratory infection and cardiac complications usually result in death before 10 years of age. {ECO:0000269|PubMed:10466419, ECO:0000269|PubMed:10735634, ECO:0000269|PubMed:12559846, ECO:0000269|PubMed:1301941, ECO:0000269|PubMed:15300847, ECO:0000269|PubMed:19396826, ECO:0000269|PubMed:21394825, ECO:0000269|PubMed:24036510, ECO:0000269|PubMed:7550232, ECO:0000269|PubMed:7550242, ECO:0000269|PubMed:7951228, ECO:0000269|PubMed:8019563, ECO:0000269|PubMed:8328452, ECO:0000269|PubMed:8401515, ECO:0000269|Ref.20}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mucopolysaccharidosis 1H/S (MPS1H/S) [MIM:607015]: A form of mucopolysaccharidosis type 1, a rare lysosomal storage disease characterized by progressive physical deterioration with urinary excretion of dermatan sulfate and heparan sulfate. MPS1H/S represents an intermediate phenotype of the MPS1 clinical spectrum. It is characterized by relatively little neurological involvement, but most of the somatic symptoms described for severe MPS1 develop in the early to mid-teens, causing considerable loss of mobility. {ECO:0000269|PubMed:10466419, ECO:0000269|PubMed:10735634, ECO:0000269|PubMed:12559846, ECO:0000269|PubMed:15300847, ECO:0000269|PubMed:21394825, ECO:0000269|PubMed:7550232, ECO:0000269|PubMed:7550242, ECO:0000269|PubMed:8401515}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mucopolysaccharidosis 1S (MPS1S) [MIM:607016]: A mild form of mucopolysaccharidosis type 1, a rare lysosomal storage disease characterized by progressive physical deterioration with urinary excretion of dermatan sulfate and heparan sulfate. Patients with MPS1S may have little or no neurological involvement, normal stature and life span, but present development of joints stiffness, mild hepatosplenomegaly, aortic valve disease and corneal clouding. {ECO:0000269|PubMed:12559846, ECO:0000269|PubMed:15300847, ECO:0000269|PubMed:19396826, ECO:0000269|PubMed:21394825, ECO:0000269|PubMed:25256405, ECO:0000269|PubMed:7550232, ECO:0000269|PubMed:7550242, ECO:0000269|PubMed:8213840}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0988

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.278

Gene Damage Prediction

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