Image Credit: University of Manchester
Scientific Frontline: Extended "At a Glance" Summary: IDUA Gene Mutations and Retinitis Pigmentosa
The Core Concept: Hypomorphic mutations in the IDUA gene, typically known for causing the severe childhood metabolic disorder mucopolysaccharidosis type I (MPS I), have been discovered to cause retinitis pigmentosa, a form of inherited blindness in adults.
Key Distinction/Mechanism: Unlike classic MPS I, which results from severe genetic faults and affects multiple organ systems, this milder presentation stems from faults that leave behind a tiny fraction (0.5 to 2 percent) of normal enzyme activity. This residual activity protects most organs but fails to support the retina, likely due to the eye's exceptionally high energy demands and reliance on cellular recycling machinery.
Origin/History: The connection was established in an October 2026 international study co-led by the University of Manchester, University College London, and the Greenwood Genetic Center, and published in The American Journal of Human Genetics.
Major Frameworks/Components:
- IDUA Gene: Provides instructions for producing an enzyme essential for cellular recycling and metabolic function.
- Retinitis Pigmentosa: A group of rare, genetic disorders that involve a breakdown and loss of cells in the retina.
- Hypomorphic Genotypes: Milder combinations of gene faults that reduce, but do not completely eliminate, enzyme activity by disrupting splicing instructions or directly lowering function.
- Mucopolysaccharidosis Type I (MPS I): A rare, severe, systemic metabolic disorder traditionally associated with complete IDUA gene failure.
Branch of Science: Genetics, Ophthalmology, and Molecular Biology.
Future Application: This discovery will refine genetic screening programs for newborns and improve the diagnostic accuracy of genetic testing panels for inherited retinal diseases by including IDUA and related metabolic genes.
Why It Matters: The findings demonstrate that a single gene can produce drastically different disease outcomes depending on residual enzyme activity, offering critical diagnostic closure to patients and opening pathways for early treatments to preserve vision.
Faults in a gene known for causing a devastating childhood metabolic illness can also cause a form of inherited blindness in adults, an international study co-led by scientists at the University of Manchester, University College London, and the Greenwood Genetic Center in the United States has found.
In the first study of its kind, published in The American Journal of Human Genetics, the scientists show how changes in this gene can cause a much milder disease than previously known.
They identified that in 14 patients with retinitis pigmentosa, the condition was caused by certain combinations of faults in a gene called IDUA.
The gene is normally associated with mucopolysaccharidosis type I (MPS I), a rare disorder that can cause severe physical disability, heart problems, skeletal abnormalities, and shortened life expectancy.
Yet several of the patients in the study showed no signs of the disorder despite detailed medical assessments and follow-up into their forties, fifties, sixties, and seventies.
Their failing eyesight was the first, and sometimes only, clue to an underlying health problem.
The findings suggest some people with retinitis pigmentosa may actually have an extremely mild form of a metabolic disease that has gone unrecognized for decades.
"This study shows that the same gene can cause dramatically different disease outcomes, depending on how much of its related enzyme activity remains." —Author name, job title, department/school/institute/center
The discovery expands our understanding of MPS I and reveals that the condition can exist in a much milder form than previously thought.
None of the patients carried the combinations of severe genetic faults normally seen in classic MPS I.
Instead, they carried milder combinations of gene faults in IDUA.
Through a series of lab experiments, the scientists found these milder faults act in different ways—some directly reducing the enzyme's activity, others disrupting the gene's splicing instructions—but in each case leaving behind only a tiny fraction, as little as 0.5 to 2 percent, of normal function.
The scientists suspect this tiny amount of residual activity may be enough to protect most organs from damage while leaving the retina vulnerable.
One theory is that the eye may be especially sensitive to defects in the body's cellular recycling machinery because of its exceptionally high energy demands.
The findings could have implications for genetic screening programs designed to identify rare diseases, including MPS I, in newborn babies.
They also underline the importance of including IDUA and related metabolic genes in genetic testing for inherited retinal diseases.
Lead author Dr. Siying Lin from the University of Manchester said, "This study shows that the same gene can cause dramatically different disease outcomes, depending on how much of its related enzyme activity remains.
"In some patients, we found almost no evidence of the devastating multisystem disorder typically associated with IDUA; their disease appeared confined to the retina, the mildest presentation we've seen to date.
"These findings broaden the recognized spectrum of disease, improve diagnosis for patients with inherited blindness, and provide important clues about why the retina appears especially susceptible to even very small reductions in enzyme function.
"We hope they will help clinicians identify hitherto unrecognized cases of IDUA-related disease and pave the way for future treatments aimed at preserving vision before irreversible damage occurs."
Published in journal: The American Journal of Human Genetics
Authors: Siying Lin, Seok-Ho Yu, Andrew C. Browning, Riccardo Sangermano, Andrzej B. Poplawski, Karolina M. Stepien, Peter Kiraly, Anna R. Ridgeway, Patrick Rump, Marianthi Karali, Francesca Simonelli, Laura K. Finnegan, G. Jane Farrar, Naomi Chadderton, Paul F. Kenna, Emma Duignan, Eleanor McCance, M. Dominik Fischer, Robin Lachmann, Yael Finezilber, Shaun M. Leo, Anthony G. Robson, Nishan Guha, Elaine Murphy, Sian Sperring, Kim Rodenburg, Aleksandr Jestin, Lonneke Haer-Wigman, Jan Willem R. Pott, Marlies M.B. Habing, Emily M. Place, Rachel M. Huckfeldt, Sandro Banfi, Marcela Votruba, Kinga M. Bujakowska, Heather Flanagan-Steet, Omar A. Mahroo, Andrew R. Webster, Susanne Roosing, Richard Steet, and Gavin Arno
Source/Credit: University of Manchester | Michael Addelman
Edited by: Scientific Frontline
Reference Number: gen100826_01