Genetic landscape of Leber's hereditary optic neuropathy: reflection on pathogenic mechanisms

Summary Leber's Hereditary Optic Neuropathy (LHON) is a mitochondrial disease due to homoplasmic mtDNA point mutations in complex I, affecting prevalently young males with incomplete penetrance. We recently documented that increase of mitochondrial biogenesis drives incomplete penetrance in LHON, further enhanced by estrogen protection in females. To shed light on nuclear genetic modifiers of LHON penetrance, we combined linkage analysis and association studies with tag and functional SNPs, MitoExome and microarray expression analysis. After computation of relevant co-variates (age, sex, smoke and mtDNA copy number) we obtained a list of candidate genes, the most interesting being implicated in ROS detoxification, mitochondrial biogenesis and cell quality control. A prevalent role of tobacco smoking in penetrance also emerged from our studies, showing that tobacco toxicity triggers LHON by depressing mtDNA copy number and oxidative phosphorylation. Overall, our results indicate that penetrance in LHON is modulated by variants in different genes rather than by a single mutation, and that a complex interaction with environmental factors such as tobacco smoking plays also a major role, representing a confounder for genetic studies. Supported by Telethon-Italy, grant #GGP11182 to VC.