Hypomorphic IDUA genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type I

Lin, Siying, Yu, Seok-Ho, Browning, Andrew C., Sangermano, Riccardo, Poplawski, Andrzej B. and Votruba, Marcela ORCID: https://orcid.org/0000-0002-7680-9135 2026. Hypomorphic IDUA genotypes are associated with retinitis pigmentosa in individuals without syndromic mucopolysaccharidosis type I. American Journal of Human Genetics 10.1016/j.ajhg.2026.09.008

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Abstract

Bi-allelic variants in IDUA classically cause mucopolysaccharidosis type I (MPS I), a multisystem lysosomal storage disorder. This study describes 14 individuals from 12 families presenting with retinitis pigmentosa, later attributed to bi-allelic IDUA genotypes. Notably, seven individuals, despite comprehensive systemic assessments, showed no features consistent with MPS I at last assessment (aged 46–73 years). Leukocyte α-L-iduronidase activity was reduced but not abolished across all individuals assessed (n = 9), supporting a shared mechanistic basis for the mild, retina-predominant, or exclusively retinal phenotype. No individual carried bi-allelic null genotypes; most had a loss-of-function allele paired with a missense variant, consistent with an overall hypomorphic genotype. Variant-level functional assays, using a cell-based expression platform assessing enzyme activity and protein abundance to derive relative specific activity (RSA), showed that several missense alleles confer very low residual activity and/or impaired abundance/processing, with RSA typically in the ∼0.5%–1.5% range. The recurrent missense c.298A>G (p.Arg100Gly) variant showed no protein or catalytic effect; targeted long-read transcript analysis instead demonstrated predominant loss-of-function mis-splicing with a small fraction of correctly spliced transcript (∼1%–2%), explaining residual activity in vivo. Together, these data expand the phenotypic spectrum of IDUA-associated disease to include late-onset retinal-predominant or apparently isolated retinitis pigmentosa and indicate that residual enzyme activity likely contributes to systemic sparing, highlighting the value of integrated genomic, biochemical, and functional analyses to advance understanding in attenuated metabolic disease.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Optometry and Vision Sciences
Additional Information:	Full list of authors: https://doi.org/10.1016/j.ajhg.2026.09.008
Publisher:	Cell Press
ISSN:	0002-9297
Date of First Compliant Deposit:	12 October 2026
Date of Acceptance:	15 September 2026
Last Modified:	12 Oct 2026 10:45
URI:	https://orca.cardiff.ac.uk/id/eprint/190136

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