IDUA – Mucopolysaccharidosis

The alpha-L-iduronidase gene (IDUA) encodes the lysosomal enzyme α-L-iduronidase essential for dermatan and heparan sulfate degradation. Deficiency of IDUA leads to mucopolysaccharidosis type I, a subset of mucopolysaccharidosis disorders with multisystemic glycosaminoglycan accumulation.

IDUA-related mucopolysaccharidosis is inherited in an autosomal recessive manner, requiring pathogenic variants on both alleles. A 15-year Italian cohort identified 147 patients with IDUA deficiency among 297 referrals, confirming IDUA variants in half of suspected MPS cases ([PMID:8412008]). Subsequent series across Indian, Algerian, European, and other populations have expanded the proband count to over 325, reinforcing the robustness of this association.

The IDUA variant spectrum is highly heterogeneous, comprising nonsense (e.g., c.1205G>A (p.Trp402Ter)), missense (c.1709A>T (p.Asp570Val)), splice-site (e.g., c.1524+1G>C), and small insertion/deletion alleles. Recurrent alleles such as p.Pro533Arg and p.Trp402Ter have been observed in multiple cohorts, reflecting potential founder effects and mutation hotspots.

Although detailed family segregation data are limited, co-segregation of IDUA pathogenic variants with disease phenotype has been documented in individual kindreds, including a homozygous p.Met1Thr change in a Chinese family with classic MPS I ([PMID:37347427]).

Functional studies corroborate a loss-of-function mechanism: cell-based expression assays of mutant alleles show markedly reduced enzyme activity, and animal models such as IDUA-morpholino zebrafish exhibit glycosaminoglycan storage phenotypes that are rescued by wild-type human IDUA mRNA ([PMID:37347427]). A W392X knock-in mouse faithfully recapitulates the Hurler syndrome phenotype with GAG accumulation and skeletal abnormalities ([PMID:19751987]).

Integration of extensive genetic, biochemical, and animal model data establishes a definitive causal relationship between IDUA variants and mucopolysaccharidosis. IDUA genetic testing should be a standard component of the diagnostic workup for MPS, enabling early initiation of enzyme replacement or hematopoietic stem cell transplantation to mitigate irreversible manifestations.

References

• Journal of inherited metabolic disease • 1993 • Biochemical diagnosis of mucopolysaccharidoses: experience of 297 diagnoses in a 15-year period (1977-1991) PMID:8412008
• Annals of the New York Academy of Sciences • 2023 • Identification of an α-l-iduronidase (IDUA) M1T mutation in a Chinese family with autosomal recessive mucopolysaccharidosis I PMID:37347427
• 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
• Investigacion clinica • 2014 • Mutation c.1190-1delG/N in intron 8 and c.1708G>C/N in exon 12 not reported in the IDUA gene developed a clinical phenotype of Scheie syndrome PMID:25558755

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