Summary: Researchers have identified a new genetic cause of hereditary optic atrophy — a degenerative condition of the optic nerve that leads to progressive vision loss — by discovering a recurrent missense mutation in the PPIB gene. PPIB encodes peptidylprolyl isomerase B, an enzyme involved in protein folding and quality control. The mutation disrupts mitochondrial function in patient cells, linking this gene to the mechanisms that underlie optic nerve degeneration.
The variant was first discovered in a large Austrian family and later confirmed in additional unrelated families worldwide. These findings improve the genetic diagnosis of unexplained optic atrophy and provide a basis for more accurate counseling and tailored medical follow-up for affected families.
Key Facts:
- New gene implicated: A recurrent missense variant in the PPIB gene is now identified as a cause of hereditary optic atrophy.
- Mitochondrial dysfunction: Patient-derived cells show altered mitochondrial morphology and subtle respiratory chain defects, consistent with mitochondrial involvement in optic nerve disease.
- Diagnostic impact: This discovery helps explain a portion of previously unsolved cases and will aid genetic testing strategies for optic atrophy.
Source: University of Vienna
Overview
A collaborative research team from the Medical University of Vienna and the Medical University of Graz has identified a previously unrecognized genetic cause of autosomal dominant optic atrophy. Their study, published in Genetics in Medicine, describes a heterozygous missense variant in PPIB (NM_000942.5:c.538C>T p.(Arg180Trp)) that segregates with optic atrophy in multiple affected family members.
The investigation began with genetic testing of a multi-generation Austrian family in which seven individuals were affected by optic atrophy. Genome-wide and exome sequencing revealed the PPIB variant, prompting further searches of archived genomic data. In total, 19 affected individuals from nine families were found to carry the same variant, supporting a recurrent, disease-causing role for this change.
PPIB encodes an enzyme that assists protein folding and participates in the removal of misfolded proteins. Functional studies using cultured skin fibroblasts from affected people showed that the variant alters mitochondrial morphology and produces subtle defects in cellular respiration. Because mitochondrial dysfunction is a frequent feature of many known forms of hereditary optic atrophy, these findings support a pathogenic link between PPIB dysfunction and degeneration of retinal ganglion cells.
Clinical features and implications
PPIB-associated optic atrophy presents with a slowly progressive decline in visual acuity, central scotomas, and thinning of inner retinal layers on imaging, similar to other autosomal dominant forms of the disease. Symptom onset was mostly in adulthood (median age 36), and clinical severity varied among individuals.
Identifying PPIB as an optic atrophy gene has direct clinical relevance: it provides a molecular diagnosis for patients who previously lacked one and allows clinicians to offer targeted genetic counseling, anticipate potential disease progression, and personalize follow-up care. Given that roughly 60% of individuals with optic atrophy have no identified genetic cause, adding PPIB to diagnostic gene panels can reduce that proportion and improve patient management.
Research methods and next steps
The study combined exome sequencing of large pedigrees with functional assays in patient-derived fibroblasts. These experiments demonstrated segregation of the PPIB variant with disease and revealed mitochondrial abnormalities that likely contribute to optic nerve vulnerability. Future research will explore the precise molecular mechanisms by which PPIB variants impair mitochondrial function and whether other variants in PPIB or related pathways cause optic atrophy.
Frequently asked questions
Q: What did the researchers discover about hereditary vision loss?
A: They identified a recurrent missense mutation in the PPIB gene that is associated with adult-onset autosomal dominant optic atrophy, expanding the list of genes known to cause this condition.
Q: How does the PPIB mutation affect vision?
A: The variant interferes with protein folding and cellular protein quality control, which in patient cells results in altered mitochondrial shape and subtle respiratory chain impairments. These mitochondrial disturbances likely lead to progressive degeneration of the retinal ganglion cells that form the optic nerve.
Q: Why is this discovery important for treatment and counseling?
A: By providing a clear genetic diagnosis, the finding enables earlier identification of affected individuals, better-informed genetic counseling for families, and improved tailoring of clinical monitoring. It also offers a new target for research into therapeutic strategies aimed at preserving vision.
About this research
Author: Karin Kirschbichler
Source: University of Vienna
Contact: Karin Kirschbichler – University of Vienna
Image credit: Neuroscience News
Original research: A recurrent missense variant in the PPIB gene encoding peptidylprolyl isomerase B underlies adult-onset autosomal dominant optic atrophy, Wolfgang M. Schmidt et al., Genetics in Medicine (open access).
Abstract (condensed)
Purpose: Hereditary optic atrophy is a major cause of vision loss and is linked to many genes, especially those affecting mitochondrial function. However, a substantial fraction of cases remain genetically unexplained.
Methods: Exome sequencing in a large pedigree and additional families identified candidate variants, followed by functional studies of mitochondrial function in patient-derived fibroblasts.
Results: A heterozygous missense variant in PPIB (c.538C>T; p.Arg180Trp) segregated with isolated optic atrophy in 19 individuals from nine families. Clinical features include adult-onset visual decline, central scotoma, and inner retinal thinning. Patient fibroblasts showed altered mitochondrial morphology and subtle respiratory chain defects.
Conclusions: The recurrent PPIB variant segregates with autosomal dominant optic atrophy and is likely pathogenic through compromised mitochondrial function. These results expand the set of genes implicated in optic atrophy and support the inclusion of PPIB in genetic testing panels for the disease.