A recurrent missense variant in the PPIB gene encoding peptidylprolyl isomerase B underlies adult-onset autosomal dominant optic atrophy.

Purpose: Hereditary optic atrophy (OA) represents one of the leading causes of blindness. A relatively large number of genes, many of which are implicated in mitochondrial function, are known to be involved in OA. For many affected individuals, however, a genetic cause still cannot be identified.

Methods: In large pedigree and additional families, exome sequencing (ES) was used to identify a genetic cause in individuals with so far genetically unresolved OA. Subsequently, mitochondrial function was studied in cultured dermal fibroblasts.

Results: ES revealed a heterozygous missense variant in PPIB [NM_000942.5:c.538C>T p.(Arg180Trp)], encoding peptidylprolyl isomerase B, which segregated with clinically isolated OA in 19 individuals from 9 families. PPIB-associated OA involves an insidious reduction in visual acuity, central scotoma and inner retinal layer thinning consistent with other autosomal dominant OAs. Age of symptom onset was mostly in adulthood (median: 36 years), and severity of clinical manifestation was variable. Patient-derived fibroblasts revealed altered mitochondrial morphology as well as subtle respiratory chain defects.

Conclusions: The PPIB variant segregates with OA, which might be caused by compromised mitochondrial function. While future studies are needed to study the exact pathomechanistic role of PPIB, insights from this work broaden the knowledge of genes implicated in autosomal dominant OA.