The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) is a common cause of bilateral o ptic nerve disease. The majority of LHON patients harbour one of three poin t mutations of the mitochondrial DNA (mtDNA) complex I, or NADH:ubiquinone oxidoreductase (ND) genes (G11778A in ND4, G3460A in ND1, T14484C in ND6). As a consequence, screening for these mutations has become part of the rout ine clinical investigation of young adults who present with bilateral optic neuropathy, and the absence of these mutations is interpreted as indicatin g there is a low likelihood that an optic neuropathy is LHON. However, ther e are many individuals who develop the clinical features of LHON but who do not harbour one of these primary LHON mutations. We describe two LHON pedi grees that harbour the same novel point mutation within the mtDNA ND6 gene (A14495G). This mutation was heteroplaslmic in both families, and sequencin g of the mitochondrial genome confirmed that the mutation arose on two inde pendent occasions. This is the seventh mutation in the ND6 gene that causes optic neuropathy, indicating that this gene is a hot spot for LHON mutatio ns. Protein modelling studies indicate that all of these pathogenic mutatio ns lie within close proximity to one another in a hydrophobic cleft or pock et. This is the first evidence for a relationship between a specific diseas e phenotype and a specific structural domain within a mitochondrial respira tory chain subunit. These findings suggest that the mtDNA ND6 gene should b e sequenced in all patients with LHON who do not harbour one of the three c ommon LHON mutations.