IDUA – Mucopolysaccharidosis Type I

Alpha-L-iduronidase, encoded by IDUA, is a lysosomal glycosidase crucial for the degradation of dermatan and heparan sulfates. Biallelic pathogenic variants in IDUA lead to autosomal recessive mucopolysaccharidosis type I (MPS I), a continuum of Hurler, Hurler–Scheie, and Scheie phenotypes characterized by glycosaminoglycan accumulation in multiple tissues. Clinical features include dysostosis multiplex, coarse facial features, hepatosplenomegaly, cardiac valve thickening, corneal clouding, and variable neurocognitive involvement.

MPS I follows an autosomal recessive inheritance pattern with complete penetrance and requires biallelic loss-of-function IDUA variants. Recurrent nonsense mutations W402X and Q70X together account for over 50% of European MPS I alleles (PMID:12865757). A comprehensive study of 102 unrelated European probands confirmed pathogenic IDUA variants in all cases, establishing definitive gene–disease causality (PMID:21394825).

To date, more than 100 unique IDUA mutations have been documented, spanning missense, nonsense, frameshift, splice site, and microdeletion classes. The c.1206G>A (p.Trp402Ter) allele is the most prevalent, introducing a premature termination codon that correlates with severe Hurler syndrome (PMID:1301196). Hypomorphic missense variants such as c.266G>A (p.Arg89Gln) and c.1598C>G (p.Pro533Arg) retain residual enzyme activity and are associated with attenuated Scheie or intermediate Hurler–Scheie presentations.

Functional assays in cell models demonstrate that active site mutations (e.g., E182A, E299A) abolish α-L-iduronidase catalytic activity without compromising protein stability, supporting a two–acidic-residue mechanism (PMID:11555618). Aberrant splicing mutations and delayed precursor processing further reduce enzyme function. A knock-in mouse model carrying the analogous W392X mutation recapitulates human MPS I pathology—glycosaminoglycan storage, skeletal dysplasia, and cardiomyopathy—validating the pathogenic mechanism in vivo (PMID:19751987).

Clinically, patients present in infancy or early childhood with progressive joint stiffness, skeletal deformities, and organomegaly. Cardiovascular complications (valve thickening, cardiomyopathy), respiratory compromise, and neurodegeneration vary by genotype. Early diagnosis via enzymatic assay and targeted IDUA sequencing enables timely enzyme replacement therapy and hematopoietic stem cell transplantation, which substantially improve long-term somatic outcomes and quality of life.

In summary, extensive genetic and functional data support a definitive association between IDUA and Mucopolysaccharidosis type I. Diagnostic sequencing of IDUA reliably detects causative alleles, guiding early therapeutic intervention. Key take-home: biallelic IDUA mutations underlie autosomal recessive MPS I; prompt molecular diagnosis is critical for effective enzyme replacement and improved prognosis.

References

• Human mutation | 2011 | IDUA mutational profiling of a cohort of 102 European patients with mucopolysaccharidosis type I: identification and characterization of 35 novel α-L-iduronidase (IDUA) alleles PMID:21394825
• Molecular genetics and metabolism | 2010 | Characterization of an MPS I-H knock-in mouse that carries a nonsense mutation analogous to the human IDUA-W402X mutation PMID:19751987
• Glycobiology | 2001 | Glycosidase active site mutations in human alpha-L-iduronidase PMID:11555618
• Genetics in medicine | 2003 | Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature PMID:12865757

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