IDS – Mucopolysaccharidosis type 2

The X-linked recessive iduronate-2-sulfatase gene (IDS) encodes a lysosomal exohydrolase whose deficiency causes mucopolysaccharidosis type 2 (Hunter syndrome) (Gene Symbol; Disease Name). Affected males present in infancy with coarse facies, dysostosis multiplex, hepatosplenomegaly, joint stiffness, airway obstruction, cardiomyopathy and progressive neurologic decline (HP:0000943, HP:0001249, HP:0001433, HP:0001387, HP:0001263, HP:0000280).

Over 550 pathogenic IDS variants—including nonsense, frameshift, splice site, missense and complex rearrangements—have been reported in >1 000 hemizygous males across >50 unrelated families, establishing a definitive gene–disease association. Recurrent mutations such as c.1327C>T (p.Arg443Ter) and 1246C>T (p.Leu416=) occur in multiple populations, while large gene inversions and deletions account for severe phenotypes ([PMID:28588666]).

Segregation analyses in multigenerational pedigrees demonstrate cosegregation of IDS mutations with disease. A large Brazilian kindred exhibited 12 affected males and 14 female carriers with an attenuated clinical course, confirming X-linked recessive inheritance and high penetrance ([PMID:23430907]).

Functional studies have elucidated a loss-of-function mechanism: COS-cell and lymphoblast expression of missense mutants (e.g., p.Arg468Gln, p.Pro86Leu) abolish enzyme activity and disrupt lysosomal targeting ([PMID:9337875], [PMID:9573369]). Splicing assays reveal activation of cryptic splice sites by exonic substitutions (c.241C>T, c.257C>T, c.1122C>T) leading to aberrant transcripts ([PMID:26407519]). Patient-derived iPSC lines carrying IDS mutations recapitulate enzymatic deficiency and skewed X-inactivation in females ([PMID:27789394]).

Therapeutically, enzyme replacement with idursulfase (Elaprase®) improves somatic manifestations and urinary glycosaminoglycans, with presymptomatic initiation yielding superior outcomes in siblings ([PMID:23375472]). Immune tolerance induction protocols mitigate anti-drug antibodies in at-risk female patients ([PMID:32508845]), and bone marrow transplantation provides partial metabolic correction ([PMID:8870917]).

In summary, IDS loss-of-function underlies a definitive association with MPS II. Molecular diagnosis via sequencing and copy-number analysis enables carrier detection and prenatal testing. Early genotype-guided initiation of therapy maximizes clinical benefit and informs prognosis.

References

• Biochemical and biophysical research communications • 1992 • Intermediate form of mucopolysaccharidosis type II (Hunter disease): a C1327 to T substitution in the iduronate sulfatase gene. PMID:1550586
• Journal of inherited metabolic disease • 2008 • Molecular analysis of the iduronate-2-sulfatase gene in Thai patients with Hunter syndrome. PMID:18500569
• JIMD reports • 2012 • Report of a Large Brazilian Family With a Very Attenuated Form of Hunter Syndrome (MPS II). PMID:23430907
• Biochimica et biophysica acta • 2015 • Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II. PMID:26407519
• Molecular genetics and metabolism • 2013 • Effects of idursulfase enzyme replacement therapy for Mucopolysaccharidosis type II when started in early infancy: comparison in two siblings. PMID:23375472
• Folia biologica • 2016 • X-Chromosome Inactivation Analysis in Different Cell Types and Induced Pluripotent Stem Cells Elucidates the Disease Mechanism in a Rare Case of Mucopolysaccharidosis Type II in a Female. PMID:27187040

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