USH2A

USH2A carries the instructions for usherin, an unusually large protein found in the basement membrane. The basement membrane is a thin supportive layer that sits beneath cells and helps hold tissues together. Usherin appears to be important for both the development and the ongoing maintenance of the retina and the inner ear. Because of this dual role, USH2A changes can affect vision alone or affect both vision and hearing. The condition is inherited in an autosomal recessive (definition: An inheritance pattern where a person needs an altered copy of a gene from both parents to be affected. Parents with only one copy are usually unaffected carriers.) pattern, which means a person usually has changes in both copies of the gene for disease to develop. The gene is also known by names such as RP39, USH2, and USHRN in older reports.

USH2A changes most often lead to retinitis pigmentosa, a rod-cone dystrophy in which the light-sensing rod cells are affected first, followed by the cone cells. This typically causes difficulty seeing in the dark and a gradual narrowing of side (peripheral) vision, with central vision often affected later. USH2A is the leading genetic cause of autosomal recessive (definition: An inheritance pattern where a person needs an altered copy of a gene from both parents to be affected. Parents with only one copy are usually unaffected carriers.) retinitis pigmentosa. Some people with USH2A changes have retinitis pigmentosa on its own, while others have Usher syndrome (definition: A genetic condition that causes both retinitis pigmentosa and hearing loss, sometimes with balance problems.) type 2, in which the retinal disease is accompanied by hearing loss that is usually present from early life. In laboratory studies using patient-derived retinal tissue models, the syndromic form was linked more strongly to cone cell (definition: A type of photoreceptor used for color vision and fine detail, mostly in central and daytime vision.) effects, and a higher proportion of people with the syndromic form showed atrophy of the macula, the central part of the retina. Age of onset, severity, and rate of progression vary from person to person and cannot be predicted from the gene name alone.

USH2A is repeatedly reported as one of the most common causative genes in large studies of inherited retinal disease across different countries, including cohorts from Korea, Argentina, Scotland, and the United States. How often USH2A appears varies across populations, but it is consistently a frequent cause of retinitis pigmentosa. The variant c.2299delG is the most frequent single USH2A change identified worldwide, and mutations in a region called exon 13 are the target of several experimental therapies. A systematic review and meta-analysis of hundreds of genotypes confirmed that the p.C759F variant is a genuine disease-causing change that acts in a recessive manner. Genetic subtype and certain electroretinogram (definition: A test (often abbreviated ERG) that measures the retina's electrical response to light, used to check how well photoreceptors are working.) measurements have been shown to help predict how quickly retinitis pigmentosa progresses, which can be useful for counseling.

It is not yet fully understood why some people with USH2A changes develop retinitis pigmentosa alone while others develop Usher syndrome (definition: A genetic condition that causes both retinitis pigmentosa and hearing loss, sometimes with balance problems.) with hearing loss, and no reliable rule links a specific variant to a specific outcome. Laboratory models suggest that molecular changes may begin before any symptoms appear, but the earliest events in human disease are still being defined. A long-term supplementation trial found that a general vitamin A benefit was not detectable across all types of retinitis pigmentosa, while vitamin E appeared harmful and should be avoided. That study was not a USH2A-specific treatment trial, so it does not establish any supplement as a gene-specific management for USH2A.

No therapy targeting USH2A has been approved, but the gene is an active focus of research. One approach uses antisense oligonucleotides, small molecules designed to bypass a faulty section of the gene's message; the investigational drug QR-421a, also called ultevursen, targets changes in exon 13 and has been evaluated in early human trials. Because the USH2A gene is very large, standard gene-replacement viruses cannot carry the whole gene, so scientists have tested alternative delivery methods such as non-viral vectors that carried the full-length gene in cells, patient-derived cells, and zebrafish. Other laboratory work has explored CRISPR (definition: A gene-editing technology that can find and change a specific, targeted spot in a cell's DNA.)-based RNA editing to correct a common USH2A change, restoring the usherin protein in cultured cells and in mice. Researchers have also built human retinal organoids, miniature lab-grown retina-like tissues, to study how USH2A disease develops and to test potential treatments. These laboratory and animal findings are steps in research and are not available treatments. An exon-skipping strategy delivered by a single injection has been described in retinal and inner-ear organoids as a possible future direction, but it remains preclinical (definition: Research done in cells or animals, before a treatment is considered ready to be studied in people.).

• Genetic subtype and electroretinogram predict progression

  Analysis of human clinical trial data with added genetic testing.

  What was found:

  Genetic subtype, including USH2A, and a baseline electroretinogram measurement independently predicted progression rate; a general vitamin A benefit was not detectable, and vitamin E remained harmful.

  Why it matters:

  It supports using genetics and functional testing for prognosis and cautions against assuming supplements help everyone.

  Limitation: The original trial was not designed around USH2A, so gene-specific conclusions are limited.

• Different USH2A variants produce different retinal patterns in lab models

  Laboratory research using patient-derived cells and organoids, plus supporting clinical observation.

  What was found:

  Non-syndromic RP models showed impaired photoreceptor development, while Usher syndrome models showed an unexpected effect on cone cells, and macular atrophy was more common in people with the syndromic form.

  Why it matters:

  This helps explain why USH2A can cause different conditions and provides tools to test whether variants are harmful and whether therapies work.

  Limitation: Organoids are simplified models and cannot fully reproduce a living human retina over time.

• Human retinal organoids model USH2A rod-cone dystrophy

  Laboratory research using human stem cell-derived organoids.

  What was found:

  Both models showed early loss of rod photoreceptors followed by broader degeneration, and molecular changes appeared before obvious cell loss.

  Why it matters:

  It suggests disease processes may start before symptoms appear, which could guide when future treatments are given.

  Limitation: Findings are from lab-grown tissue, not from treated patients, and animal models did not reproduce the human features.

• Toward gene and RNA therapies for a very large gene

  Preclinical laboratory and animal research.

  What was found:

  The non-viral approach restored usherin in patient cells and zebrafish, and RNA editing restored correctly located usherin protein in mice after correcting a common variant.

  Why it matters:

  USH2A is too large for standard gene-replacement viruses, so these strategies address a key obstacle to future treatment.

  Limitation: Neither approach has been tested in people, and effects in humans are unknown.

• Confirming that the p.C759F variant causes disease

  Systematic review and meta-analysis of published human data.

  What was found:

  The variant was strongly enriched in affected people and behaved as a recessive disease-causing change, including in people carrying two copies.

  Why it matters:

  Clear variant interpretation is essential for accurate diagnosis and counseling.

  Limitation: It combines data from many studies of varying quality rather than a single controlled cohort.

Unlike many retinal genes, USH2A can affect hearing as well as vision, because in Usher syndrome (definition: A genetic condition that causes both retinitis pigmentosa and hearing loss, sometimes with balance problems.) type 2A the retinal disease occurs alongside hearing loss that is usually present from early life. Families may find it helpful to know that hearing can be supported with hearing aids or, in some cases, cochlear implants, and that combined hearing and vision changes deserve coordinated attention. Because USH2A is inherited recessively, siblings and other close relatives may wish to discuss carrier status and testing with a genetic counselor.

• Do my USH2A test results point toward non-syndromic retinitis pigmentosa or Usher syndrome type 2A?
• Are my specific variants located in exon 13, which some experimental therapies are designed around?
• Would a hearing and balance evaluation be helpful given the USH2A diagnosis?
• What tests can help track how my retinal disease is progressing over time?
• Are there natural history studies or registries that might be relevant to me?
• What do my results mean for other members of my family?

Confirming the exact USH2A variants involved through genetic testing and counseling can clarify the diagnosis and inform discussions about prognosis and research options. Because USH2A can involve hearing as well as vision, a hearing evaluation may be worth discussing with your care team if it has not already been done. For personalized screening of studies related to USH2A, RP Hope's Clinical Trials Finder is the appropriate place to start.