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IDUA
alpha-L-iduronidase
The IDUA gene provides instructions for producing the alpha-L-iduronidase enzyme, which is crucial for the breakdown of certain complex sugar molecules within cells. The IDUA gene encodes the alpha-L-iduronidase enzyme, vital for the cellular breakdown of glycosaminoglycans (GAGs).
IDUA is located on the short (p) arm of chromosome 4, at band 4p16.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The IDUA gene, also known as alpha-L-iduronidase, is integral to the proper functioning of cellular lysosomes. These lysosomes are specialised compartments within cells that are responsible for recycling and breaking down various molecules. The enzyme produced by the IDUA gene plays a critical role in this process, specifically targeting large sugar molecules.
Pathogenic variants in the IDUA gene are associated with Mucopolysaccharidosis type I (MPS I), an autosomal recessive inherited condition. This condition arises when the enzyme's activity is reduced or absent, leading to the accumulation of specific sugar molecules within the body's cells and tissues.
What the gene does
The primary function of the IDUA gene is to provide the genetic blueprint for alpha-L-iduronidase, a lysosomal enzyme. This enzyme is essential for the hydrolysis, or breakdown using water, of specific complex sugar molecules known as glycosaminoglycans (GAGs). Specifically, alpha-L-iduronidase acts on unsulfated alpha-L-iduronic acid components found in two important GAGs: heparan sulfate and dermatan sulfate.
These GAGs are long chains of sugar molecules that contribute to the structure of connective tissues throughout the body. Without functional alpha-L-iduronidase, heparan sulfate and dermatan sulfate cannot be properly broken down and recycled. Instead, they accumulate within the lysosomes, leading to cellular dysfunction and the clinical manifestations observed in Mucopolysaccharidosis type I.
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Chromosome location
The IDUA gene is situated on the short arm of chromosome 4, at position 16.3, denoted as 4p16.3. This precise genomic location helps in identifying the gene within the human genome and understanding its inheritance patterns.
Protein structure
The alpha-L-iduronidase protein consists of 653 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the IDUA gene can alter the production or function of the alpha-L-iduronidase enzyme. More than 100 different types of pathogenic variants have been identified that cause Mucopolysaccharidosis type I. These changes often involve a single DNA building block, which can significantly impair or completely eliminate the enzyme's activity.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1146dup | p.Arg383fs | Pathogenic | ★★★☆ | Mucopolysaccharidosis type 1 |
c.1587_1588dup | p.Leu530fs | Pathogenic | ★★★☆ | Mucopolysaccharidosis type 1 |
c.1593del | p.Leu532fs | Pathogenic | ★★★☆ | Mucopolysaccharidosis type 1 |
c.1727+2T>G | - | Pathogenic | ★★★☆ | Mucopolysaccharidosis type 1 |
c.385+1G>A | - | Pathogenic | ★★★☆ | Mucopolysaccharidosis type 1 |
c.501C>A | p.Tyr167Ter | Pathogenic | ★★★☆ | Mucopolysaccharidosis type 1 |
c.540_544del | p.Trp180_Glu182delinsTer | Pathogenic | ★★★☆ | Mucopolysaccharidosis type 1 |
c.568_581del | p.Asn190fs | Pathogenic | ★★★☆ | Mucopolysaccharidosis type 1 |
c.792+1G>C | - | Pathogenic | ★★★☆ | Mucopolysaccharidosis type 1 |
c.792+1G>T | - | Pathogenic | ★★★☆ | Mucopolysaccharidosis type 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the IDUA gene are the underlying cause of Mucopolysaccharidosis type I (MPS I). This condition is an inherited metabolic disorder characterised by the body's inability to break down specific complex sugar molecules. The severity of MPS I can vary, but generally, all pathogenic IDUA variants result in a reduction or complete loss of alpha-L-iduronidase enzyme function.
Inheritance pattern
Conditions caused by pathogenic IDUA variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The IDUA gene is well-recognised within the NHS Genomic Medicine Service, being featured on several UK PanelApp green lists. These include panels for Foetal anomalies, Intellectual disability, Likely inborn error of metabolism, Lysosomal storage disorder, Mucopolysaccharidosis type IH or S, Paediatric or syndromic cardiomyopathy, Rare syndromic craniosynostosis or isolated multisuture synostosis, Skeletal dysplasia, and Undiagnosed metabolic disorders, indicating its clinical significance in various diagnostic pathways.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the IDUA gene?
The IDUA gene provides instructions for creating the alpha-L-iduronidase enzyme, which is essential for breaking down specific large sugar molecules called glycosaminoglycans (GAGs) within cellular lysosomes.
What condition is linked to IDUA gene variants?
Pathogenic variants in the IDUA gene are associated with Mucopolysaccharidosis type I (MPS I), an inherited metabolic disorder resulting from the accumulation of GAGs due to insufficient enzyme activity.
How does reduced IDUA enzyme activity affect the body?
When the alpha-L-iduronidase enzyme is deficient, GAGs like heparan sulfate and dermatan sulfate accumulate in lysosomes. This build-up disrupts normal cellular function, leading to the diverse symptoms of Mucopolysaccharidosis type I.
References
- Pastores GM, Arn P, Beck M. The MPS I registry: design, methodology, and early findings of a global disease registry for monitoring patients with Mucopolysaccharidosis Type I. Molecular genetics and metabolism. 2007. PMID: 17336562
- Vijay S, Wraith JE. Clinical presentation and follow-up of patients with the attenuated phenotype of mucopolysaccharidosis type I. Acta paediatrica (Oslo, Norway : 1992). 2005. PMID: 16188808
- Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. The Journal of pediatrics. 2004. PMID: 15126981
- Terlato NJ, Cox GF. Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature. Genetics in medicine : official journal of the American College of Medical Genetics. 2003. PMID: 12865757
- Beesley CE, Meaney CA, Greenland G. Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations. Human genetics. 2001. PMID: 11735025
- Adam MP, Bick S, Mirzaa GM. Mucopolysaccharidosis Type I. 1993. PMID: 20301341