Mutation analysis of the ND6 gene in patients with Lebers hereditary optic neuropathy.

DNA sequence analysis of the gene encoding subunit 6 of the NADH-ubiquinone-oxidoreductase complex (ND6) in human mitochondria was performed in 25 independent patients who suffer from Lebers hereditary optic neuropathy (LHON). In 10 cases the well-known LHON mutation at nucleotide position (np) 14484 was detected. Furthermore, silent substitutions at np14167 and np14527 and missense mutations at np14498, np14564, np14568, and np14582 were found in individual patients. The np14498 and np14568 mutations were found in patients who present a typical clinical picture and course of LHON but lack any of the canonical mtDNA mutations. The np14568 mutation, which replaces a moderately conserved glycine by a serine residue, was observed in a single male patient and subsequently excluded in 175 independent controls. The mutation at np14498, which replaces an evolutionarily highly conserved tyrosine with a cysteine, was found in a multigeneration family with four affected members, the eldest carrying a heteroplasmic mixture of mutated and wildtype mtDNA molecules. None of 170 analyzed control subjects carried this mutation. These findings provide evidence that several allelic ND6 gene mutations may be involved in Lebers hereditary optic neuropathy.