The role of mitochondrial genome in inherited optic neuropathies

Leber's hereditary optic neuropathy (LHON) and Dominant Optic Atrophy (DOA) are common cause of vision loss. LHON is due in 90% of cases to three common point mutations in mitochondrial genome (mtDNA), affecting complex I subunit genes. In 10% LHON is associated to a rare mtDNA mutation and, for the first time, with peculiar combinations of individually non-pathogenic missense mtDNA variants. The pathogenic potential of these mtDNA haplotypes is supported by multiple evidences: the LHON phenotype is strictly inherited along maternal line; the combinations of variants are unique; the mitochondrial defect is co-transferred into the cybrid-cell model; all but one of these variants clustered along the same predicted fourth E-channel deputed to proton translocation. Hence, the definition of the pathogenic role of a specific mtDNA mutation becomes blurrier than ever and, even in the absence of a clearly established LHON primary mutation, unprecedented combinations of missense mtDNA variants, individually known as polymorphisms, may lead to reduced OXPHOS efficiency sufficient to trigger LHON. In this complex scenario, mtDNA variability itself may play a modifying role in LHON and DOA. The mtDNA was completely sequenced in largest European cohort of 119 independent probands, carrying the m.14484T>C/MT-ND6 LHON mutation. Besides the occasional finding of double mutants and multiple founder events, we confirm the association with haplogroup J root, but not with its more recent sub-clades. The phylogenetic analysis suggests a possible double role of haplogroup J: predisposing factor to mutagenesis or preserving the mutation during evolution. On the clinical ground, the penetrance of m.14484T>C/MT-ND6 mutation increases on haplogroup J, especially in females. In DOA cohorts, the relationship with mtDNA genetic variation is complex: no specific haplogroups resulted associated with DOA, neither clearly modified its clinical outcome. We only documented a minor effect of mtDNA, and nDNA played a definitely stronger role as modifier.