Lin et al., The American Journal of Human Genetics - Bi-allelic variants in IDUA classically cause mucopolysaccharidosis type I, a lysosomal storage disorder that affects many organs from childhood. This study describes 14 adults and young adults from 12 families who first came to eye clinics with retinitis pigmentosa and were later found to carry bi-allelic IDUA variants. Seven of them showed no systemic features of the disease even after detailed assessment, and enzyme activity in white blood cells was reduced but never absent. Cell-based enzyme assays and long-read RNA sequencing explain how mild, hypomorphic alleles can leave just enough enzyme to spare the body but not the retina. Key terms: IDUA, mucopolysaccharidosis type I, retinitis pigmentosa, hypomorphic variants, splicing.
Study Highlights:
Individuals aged 19 to 73 were recruited from inherited retinal disease cohorts in the UK, Ireland, Italy, the Netherlands and the United States, and none carried two null alleles; most had a loss-of-function allele paired with a missense variant. Leukocyte alpha-L-iduronidase activity was reduced but detectable in all nine individuals tested, and urine glycosaminoglycans were above normal in only half of those tested, with modest elevations. In an IDUA-knockout cell line, several missense variants, including p.His91Tyr and p.Arg383His, showed relative specific activity around 0.5% to 1.5% of wild type, with poor processing or stability. The recurrent c.298A>G variant left enzyme activity intact as a protein change, but nanopore long-read sequencing showed that it mostly causes exon 2 skipping, with only about 1.3% of reads from that allele spliced normally.
Conclusion:
Hypomorphic IDUA genotypes that leave low residual enzyme activity can cause late-onset retinitis pigmentosa with mild or apparently no systemic disease, extending the known spectrum of MPS I and arguing for including IDUA in inherited retinal disease gene panels. The cohort is small and mostly of European ancestry, systemic assessment varied in depth, and without longitudinal follow-up some individuals classed as having isolated retinal disease may still develop systemic features.
Article title:
Hypomorphic IDUA genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type I
First author:
Lin
Journal:
The American Journal of Human Genetics
DOI:
10.1016/j.ajhg.2026.09.008
Reference:
Lin, S., Yu, S.-H., Browning, A. C., et al., Roosing, S., Steet, R., and Arno, G. (2026). Hypomorphic IDUA genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type I. The American Journal of Human Genetics 113, 1-12. https://doi.org/10.1016/j.ajhg.2026.09.008
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-10-11.
QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/out...
Chapters
- (00:00:20) - Introduction: Two Faces of One Gene
- (00:01:54) - The Lysosome Crew Analogy
- (00:03:01) - Study Overview and Authors
- (00:03:44) - Understanding IDUA and MPS1
- (00:04:23) - MPS1 Severity Spectrum and Eye Involvement
- (00:05:41) - The Unclear Case of Retina-Only Disease
- (00:06:54) - Study Cohort and Methods
- (00:08:06) - Clinical Eye Workup and Testing
- (00:08:38) - Measuring Enzyme Activity in the Lab
- (00:09:44) - RNA Sequencing of a Puzzling Variant
- (00:10:18) - Genetic Findings: One Null, One Missense
- (00:10:49) - Clinical Results: Retina Affected, Body Spared
- (00:12:01) - Biochemical Results: Reduced but Not Absent
- (00:12:37) - Variant-by-Variant Activity Results
- (00:13:50) - The Recurrent Splicing Variant Mystery
- (00:14:26) - Long-Read Sequencing Reveals Leaky Splicing
- (00:15:37) - Why the Retina Fails First
- (00:16:15) - Clinical Implications for Diagnosis and Panels
- (00:16:51) - Therapeutic Implications
- (00:17:18) - Newborn Screening Dilemma
- (00:17:55) - Study Limitations
- (00:18:31) - Conclusions and Open Questions
- (00:19:31) - Closing and Credits
