IDUA – Hurler-Scheie Syndrome

IDUA (HGNC:5391) encodes the lysosomal enzyme alpha-L-iduronidase responsible for degradation of dermatan and heparan sulfates. Biallelic loss-of-function variants in IDUA cause mucopolysaccharidosis type I, with the intermediate Hurler-Scheie phenotype (MONDO:0011759) manifesting in later childhood or adulthood. The disorder follows autosomal recessive inheritance, with affected individuals often exhibiting mixed features of Hurler and Scheie syndromes. Clinically, patients present with corneal clouding, joint stiffness, valvular heart disease, left ventricular hypertrophy (HP:0001712), coronary artery atherosclerosis (HP:0001677), and abnormal heart valve morphology (HP:0001654).

Extensive genetic studies have identified over 128 unrelated patients with intermediate MPS I carrying two pathogenic IDUA alleles ([PMID:21394825]). The mutational spectrum includes >50 missense mutations, >20 nonsense mutations such as c.1206G>A (p.Trp402Ter) ([PMID:1301196]), >10 splice-site changes, and several small insertions/deletions. The common W402X allele alone accounts for ~31% of alleles in Hurler patients and is associated with severe phenotypes in homozygosity ([PMID:1301196]). A cohort of five Thai individuals with Hurler-Scheie syndrome harbored homozygous or compound heterozygous mutations including c.1960T>C (p.Ter654Arg) and c.266G>A (p.Arg89Gln) demonstrating residual enzyme activity correlating with the attenuated phenotype ([PMID:29282708]). Family studies consistently show segregation of biallelic variants with disease under an autosomal recessive model.

Functional and biochemical analyses support a loss-of-function mechanism. Site-directed mutagenesis of conserved catalytic residues, such as E182A and E299A, abolished enzyme activity despite normal expression and lysosomal targeting, confirming their roles in catalysis ([PMID:11555618]). Patient-derived fibroblasts with premature stop codons (e.g., Q70X, W402X) exhibit negligible alpha-L-iduronidase activity and glycosaminoglycan accumulation. The Idua-W392X knock-in mouse model, homologous to human W402X, recapitulates key biochemical and histopathological features of Hurler syndrome, including multisystemic GAG storage and skeletal abnormalities ([PMID:19751987]).

No significant conflicting evidence disputed the IDUA–Hurler-Scheie association. Alternative phenotypes in other lysosomal disorders are readily distinguished by enzymatic assays and molecular testing. Extensive concordance between genotype, residual enzyme activity, and clinical severity across over 20 populations underpins the specificity of this gene–disease link.

Integration of genetic and functional data establishes a definitive clinical validity for IDUA in Hurler-Scheie syndrome. Biochemical assays and sequencing of IDUA guide early diagnosis and treatment decisions, including timing of enzyme replacement therapy and hematopoietic stem cell transplantation. Carrier testing and prenatal diagnosis benefit from the well-characterized mutation spectrum. Future therapies, such as read-through agents for stop codons and gene editing, are informed by the mechanistic insights from functional studies.

Key Take-home: Biallelic IDUA variants cause autosomal recessive Hurler-Scheie syndrome via loss of alpha-L-iduronidase activity; comprehensive genotyping and functional assays are essential for diagnosis, prognosis, and therapeutic planning.

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
• Human mutation • 1992 • A common mutation for mucopolysaccharidosis type I associated with a severe Hurler syndrome phenotype PMID:1301196
• Annals of human genetics • 2018 • p.X654R IDUA variant among Thai individuals with intermediate mucopolysaccharidosis type I and its residual activity as demonstrated in COS-7 cells PMID:29282708
• Glycobiology • 2001 • Glycosidase active site mutations in human alpha-L-iduronidase PMID:11555618
• 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

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