Severity of genetic disease determined by identification of modifying factors

Genetic diseases develop due to abnormalities in a single gene. However, even within the same lineage (such as among biological siblings), the severity of symptoms can vary significantly. A collaborative research group including Doctoral Student Cong Cui and Professor Motokazu Tsujikawa (Invited Project Leader at the National Institutes of Biomedical Innovation, Health and Nutrition) of the Graduate School of Medicine at the University of Osaka, alongside Professor Yoshihiro Omori of the Graduate School of Integrated Sciences for Life at Hiroshima University, has revealed that in addition to the primary gene mutation (pathogenic gene), two specific factors regulate the severity of symptoms in the intractable genetic disease retinitis pigmentosa. The findings were published in Advanced Science.

The research group spent 12 years studying the lineages of a zebrafish model of human retinitis pigmentosa. As a result, they discovered the emergence of a lineage with extremely mild symptoms, despite carrying the exact same genetic mutation as the severe cases. It was revealed that this mild lineage occurred due to a three-base difference located in cis near the causative gene mutation. Furthermore, when the researchers repeatedly crossed this mild lineage with wild-type (normal) fish, they discovered lineages half of whose offspring reverted to a severe phenotype.

Within the descendants of these re-severed fish, half continued to develop severe symptoms while the other half remained mild. This outcome strongly indicates the presence of an additional genetic factor located in trans at a distance from the pathogenic gene. This achievement marks the world's first time that both cis and trans factors altering severity have been simultaneously identified in a genetic disease caused by a single gene mutation.

While the existence of genetic factors (modifying factors) that influence the severity of genetic diseases had previously been understood conceptually, it had never been proven outside of exceptional cases. By clarifying these two modifying factors, this study establishes a foundation for predicting and controlling the severity of illnesses, including genetic diseases.

Moving forward, these findings are expected to find applications in discovering genetic factors that dictate the symptoms, severity, and prognosis of genetic disorders, as well as in developing treatments.

Tsujikawa stated: "By meticulously observing a fish model carrying a single genetic abnormality over a 12-year period, this study has demonstrated the existence of previously unknown genetic modifying factors. This research serves as a reminder of the importance of persistence and precise observation."

Journal Information
Publication: Advanced Science
Title: Cis− and Trans-Regulatory Factors Independently Shape Phenotypic Heterogeneity of Retinitis Pigmentosa
DOI: 10.1002/advs.202520828