A MITOCHONDRIAL-DNA MUTATION AT NUCLEOTIDE PAIR-14459 OF THE NADH DEHYDROGENASE SUBUNIT-6 GENE ASSOCIATED WITH MATERNALLY INHERITED LEBER HEREDITARY OPTIC NEUROPATHY AND DYSTONIA

A five-generation Hispanic family expressing maternally transmitted Le ber hereditary optic neuropathy and/or early-onset dystonia associated with bilateral basal ganglia lesions was studied. Buffy coat mitochon drial DNA (mtDNA) from a severely affected child was amplified by the polymerase chain reaction and greater than 90% sequenced. The mtDNA pr oved to be a Native American haplogroup D genotype and differed from t he standard ''Cambridge'' sequence at 40 nucleotide positions. One of these variants, a G-to-A transition at nucleotide pair (np) 14459, cha nged a moderately conserved alanine to a valine at NADH dehydrogenase submit 6 (ND6) residue 72. The np 14459 variant was not found in any o f 38 Native American haplogroup D mtDNAs, nor was it detected in 108 A sian, 103 Caucasian, or 99 African mtDNAs. Six maternal relatives in t hree generations were tested and were found to harbor the mutation, wi th one female affected with Leber hereditary optic neuropathy being he teroplasmic. Thus, the np 14459 G-to-A missense mutation is specific t o this family, alters a moderately conserved amino acid in a complex I gene, is a unique mtDNA variant in Native American haplogroup D, and is heteroplasmic, suggesting that it is the disease-causing mutation.