Genetics in medicine : official journal of the American College of Medical Genetics · 2025
A recurrent missense variant in the PPIB gene encoding peptidylprolyl isomerase B underlies adult-onset autosomal dominant optic atrophy.
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Valentin Katharina, Kustermann Monika, Schneider Mona R, Aminfar Haleh, Vollnhofer Kathrin, Wedrich Andreas, Stapf Christoph, Bertich Martin, Ritter Markus, Mendrina Theresa, Valcanover Daniel, Berger Walter, Eckhard Margret, Sombke Andy, Lilja Stephanie V, Paquay Amina, Rosensteiner Bernhard, Schmidt Iris, Bittner Reginald E, Georgi Thomas P, Pemp Berthold, Schmidt Wolfgang M
Аннотация
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 a large pedigree and additional families, exome sequencing 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: Exome sequencing 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.
CONCLUSION: The PPIB variant segregates with OA, which might be caused by compromised mitochondrial function. Although 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.
METHODS: In a large pedigree and additional families, exome sequencing 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: Exome sequencing 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.
CONCLUSION: The PPIB variant segregates with OA, which might be caused by compromised mitochondrial function. Although 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.