An international team of researchers has identified several new genetic links to retinitis pigmentosa, a leading cause of inherited blindness affecting an estimated one in 5,000 people worldwide. The study, published February 22, 2024, in Nature Genetics, reveals that mutations in non-protein-coding DNA-previously considered “junk DNA”-can play a critical role in the advancement of the disease. This breakthrough offers a potential path toward diagnoses for the 30-50% of retinitis pigmentosa patients who currently lack a confirmed genetic cause and underscores the growing understanding of the genome’s complex role in inherited eye disorders.
A new international study has pinpointed previously unknown genetic causes of an inherited form of blindness, potentially opening avenues for improved diagnosis of genetic eye diseases. The research reveals that alterations in non-protein-coding segments of DNA can play a critical role in vision loss, a finding that expands our understanding of the genetic basis of these conditions.
Researchers at Radboud University Medical Center in the Netherlands and the University of Basel in Switzerland collaborated on the study, focusing on retinitis pigmentosa, a hereditary eye disease affecting roughly one in 5,000 people worldwide. The disease typically begins with night vision difficulties, progressing to a gradual narrowing of the visual field – often described as “tunnel vision” – and can ultimately lead to complete blindness.
The findings, published on February 22, 2024, in Nature Genetics, represent a significant step forward in unraveling the complex genetics of inherited retinal diseases. Identifying the underlying causes of these conditions is crucial for developing potential therapies and providing accurate genetic counseling.
While over 100 genes have already been linked to retinitis pigmentosa, a genetic cause remains elusive in 30–50% of patients, even after comprehensive DNA testing. The Radboudumc team aimed to address this gap in understanding.
The investigation began with a family in the United States, where a father and eight of his children were affected by blindness and other genetic health issues. Initial genetic analysis failed to identify mutations in known genes associated with retinitis pigmentosa. Further whole-genome sequencing of the family members revealed other health concerns, but the cause of the vision loss remained a mystery.
Researchers eventually identified a genetic variant in a gene called RNU4-2. This gene is unusual because it doesn’t produce a protein; instead, it produces RNA. This RNA then associates with proteins and other RNA molecules, forming a complex involved in splicing – a crucial process where genetic information is prepared before a cell makes proteins.
Although variants in RNU4-2 have previously been linked to developmental disorders, the mutation identified in this family specifically disrupts a critical point in the RNA structure, interfering with a key regulatory mechanism for the retina and ultimately leading to blindness.
Expanding their research, the team at the University of Basel analyzed the DNA of 5,000 patients with retinitis pigmentosa whose genetic cause was previously unknown. This analysis identified, in addition to RNU4-2, four other similar genes implicated in the disease. The comprehensive analysis led to a molecular diagnosis for 153 individuals from 67 families.
These genetic variants account for approximately 1.4% of previously unresolved cases of retinitis pigmentosa globally.
The discovery is particularly important because it demonstrates that non-protein-coding DNA segments can be essential in inherited retinal diseases – a concept that hadn’t been definitively proven before. This finding broadens the scope of genetic investigation for these conditions.
For the family at the center of the research, the results provided a long-awaited answer, allowing them to make informed decisions about family planning and the risk of passing on the condition. Researchers noted that identifying the genetic cause offered closure and empowered the family with crucial information.
The authors emphasize that the implications of this research extend beyond retinitis pigmentosa, highlighting the importance of analyzing non-protein-coding genes in the broader study of inherited diseases.
