title: The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy.
abstract: Leber's hereditary optic neuropathy (LHON) is a common cause of bilateral optic nerve disease. The majority of LHON patients harbour one of three point 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 routine clinical investigation of young adults who present with bilateral optic neuropathy, and the absence of these mutations is interpreted as indicating there is a low likelihood that an optic neuropathy is LHON. However, there 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 pedigrees that harbour the same novel point mutation within the mtDNA ND6 gene (A14495G). This mutation was heteroplasmic in both families, and sequencing of the mitochondrial genome confirmed that the mutation arose on two independent occasions. This is the seventh mutation in the ND6 gene that causes optic neuropathy, indicating that this gene is a hot spot for LHON mutations. Protein modelling studies indicate that all of these pathogenic mutations lie within close proximity to one another in a hydrophobic cleft or pocket. This is the first evidence for a relationship between a specific disease phenotype and a specific structural domain within a mitochondrial respiratory chain subunit. These findings suggest that the mtDNA ND6 gene should be sequenced in all patients with LHON who do not harbour one of the three common LHON mutations.
authors.affiliation: Department of Neurology, The University of Newcastle upon Tyne, Newcastle upon Tyne, King's College Hospital, London, UK.
authors.forename: P F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: D T
authors.initials: DT
authors.lastname: Brown
authors.forename: R M
authors.initials: RM
authors.lastname: Andrews
authors.forename: R
authors.initials: R
authors.lastname: Singh-Kler
authors.forename: P
authors.initials: P
authors.lastname: Riordan-Eva
authors.forename: J
authors.initials: J
authors.lastname: Lindley
authors.forename: D A
authors.initials: DA
authors.lastname: Applegarth
authors.forename: D M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: N
authors.initials: N
authors.lastname: Howell
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics*; D015418:Optic Atrophies, Hereditary / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I