Discovery of <i>PHB1</i> 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 autosomal 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 optic atrophy or a related mitochondrial disorder. This represents the first report implicating PHB1 in a Mendelian disease. Further studies are required to validate this association.