20.500.12556/DiRROS-31303 Discovery of PHB1 as a novel candidate gene in dominant optic atrophy Hereditary optic neuropathies comprise a genetically heterogeneous group of disorders caused by pathogenic variants in mitochondrial and nuclear genes. Despite increasing diagnostic yields, many patients remain without a molecular diagnosis. We report a novel candidate heterozygous variant in the PHB1 (Prohibitin 1) gene in a large family affected by autosomal dominant optic atrophy. A three-generation family with slowly progressive visual acuity loss due to optic neuropathy and an apparent auto-somal dominant pattern was clinically characterized and recruited for genetic counseling. Exome sequencing and genome-based linkage mapping were performed, alongside protein modeling and in vitro experiments to obtain functional evidence. Family-based whole-genome linkage mapping identified a heterozygous missense variant, c.440C>T (p.Ser147Phe), in PHB1 in all five affected individuals. The variant substitutes p.Ser147Phe within an evolutionarily conserved alpha-helix domain of PHB1, a mitochondrial protein with multiple roles. In silico modeling suggested that p.Ser147Phe may disrupt PHB1 stability and function through loss of hydrogen bonding, steric hindrance, and altered hydrophobic interactions. In vitro experiments suggested potential alterations in mitochondrial dynamics in variant carriers, including a changed ratio of L- OPA1 to S- OPA1 compared with non-carriers. We present initial evidence that PHB1 is a novel candidate gene potentially associated with dominant opticatrophy or a related mitochondrial disorder. This represents the first report implicating PHB1 in a Mendelian disease. Further studies are required to validate this association. PHB1 candidate genes dominant optic atrophy mitochondrial dysfunction prohibitin 1 kandidatni geni dominantna optična atrofija (DOA) mitohondrijska disfunkcija genetika medicinska oftalmologija true false false Angleški jezik Slovenski jezik Neznano 2026-07-27 09:53:06 2026-07-27 09:53:06 2026-07-28 03:47:43 0000-00-00 00:00:00 2026 0 0 str. 165-171 issue 2 Vol. 110 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 617.7:616-056.7 0009-9163 10.1111/cge.70174 279599107 RAZ_Volk_Marija_2026.pdf RAZ_Volk_Marija_2026.pdf 1 6B055B5B2150DC7363EE7FF1CCB86D94 9add9e81a8fd15bcff2a52b7c45a0167ebff019646cd905e8893946cc8572d8c 88d271ab-8990-11f1-a255-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=48389 https://onlinelibrary.wiley.com/doi/10.1111/cge.70174 1 35c8f468-8990-11f1-a255-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=48388 Univerzitetni klinični center Ljubljana 0 0 0