New PPIB Gene Variant Identified as Cause of Hereditary Optic Atrophy

A collaborative research team from the Medical University of Vienna and the Medical University of Graz has identified a previously unknown genetic cause of hereditary optic atrophy, a degenerative condition of the optic nerve that leads to progressive vision loss. The findings, published in Genetics in Medicine, offer new insights into the genetic diagnosis and disease mechanisms of optic atrophy.

Discovery of the PPIB Gene Variant

The breakthrough emerged from the genetic investigation of a large Austrian family in which seven members across three generations were affected by optic atrophy. Using genome-wide sequencing, researchers discovered a previously undescribed variant in the PPIB gene (peptidylprolyl isomerase B).

This gene is responsible for encoding an enzyme that assists proteins in achieving their correct structure and helps degrade misfolded proteins. Functional studies in cultured cells from affected individuals demonstrated that this variant impairs mitochondrial activity, a hallmark found in most known hereditary optic atrophies.

Dr. Wolfgang M. Schmidt from the Center for Anatomy and Cell Biology at MedUni Vienna, who led the study, commented:

"We have succeeded in describing the PPIB gene as a new optic atrophy gene."

Broader Genetic Significance

By further analyzing archived genome data, the team identified 12 additional affected individuals from eight unrelated families who also carried the same PPIB gene mutation. This strengthens the association between the variant and the development of optic atrophy.

Co-study leader Dr. Thomas P. Georgi from the Department of Ophthalmology at MedUni Graz added:

"The identification of this genetic variant creates the possibility of a genetic diagnosis, which has been lacking in many cases. This is vital for offering tailored medical guidance and care to affected families."

A Step Forward in Diagnosing Unsolved Cases

Optic atrophy results in progressive degeneration of retinal ganglion cells, which transmit visual signals from the retina to the brain. Initial symptoms typically include reduced visual acuity, impaired color vision, and central visual field defects. While approximately 20 genetic forms of optic atrophy have been identified, most linked to mitochondrial dysfunction, the genetic cause remains unknown in about 60% of cases.

The discovery of the PPIB gene variant helps fill a portion of this diagnostic gap and could enable genetic testing and early diagnosis for more individuals.

Looking Ahead: Functional Studies and Future Implications

The study was a collaborative effort involving the Center for Anatomy and Cell Biology, the Department of Ophthalmology and Optometry, and the Center for Cancer Research at the Medical University of Vienna, along with the University Eye Clinic at the Medical University of Graz.

Future research will investigate how the PPIB variant affects cellular metabolism in more detail and explore whether other mutations in this gene are implicated in optic atrophy.

Reference:

Katharina Valentin et al, A recurrent missense variant in the PPIB gene encoding peptidylprolyl isomerase B underlies adult-onset autosomal dominant optic atrophy, Genetics in Medicine (2025). DOI: 10.1016/j.gim.2025.101595