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

Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6206-10. doi: 10.1073/pnas.91.13.6206.


A five-generation Hispanic family expressing maternally transmitted Leber hereditary optic neuropathy and/or early-onset dystonia associated with bilateral basal ganglia lesions was studied. Buffy coat mitochondrial DNA (mtDNA) from a severely affected child was amplified by the polymerase chain reaction and greater than 90% sequenced. The mtDNA proved to be a Native American haplogroup D genotype and differed from the standard "Cambridge" sequence at 40 nucleotide positions. One of these variants, a G-to-A transition at nucleotide pair (np) 14459, changed a moderately conserved alanine to a valine at NADH dehydrogenase subunit 6 (ND6) residue 72. The np 14459 variant was not found in any of 38 Native American haplogroup D mtDNAs, nor was it detected in 108 Asian, 103 Caucasian, or 99 African mtDNAs. Six maternal relatives in three generations were tested and were found to harbor the mutation, with one female affected with Leber hereditary optic neuropathy being heteroplasmic. Thus, the np 14459 G-to-A missense mutation is specific to 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.

Publication types

  • Case Reports
  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenine
  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Child
  • Codon / genetics
  • Conserved Sequence
  • DNA, Mitochondrial / genetics*
  • Female
  • Guanine
  • Haplotypes / genetics
  • Hispanic or Latino / genetics
  • Humans
  • Indians, North American / genetics
  • Macromolecular Substances
  • Male
  • Molecular Sequence Data
  • NADH Dehydrogenase / genetics*
  • Optic Atrophies, Hereditary / enzymology
  • Optic Atrophies, Hereditary / genetics*
  • Pedigree
  • Phylogeny
  • Point Mutation*
  • Restriction Mapping


  • Codon
  • DNA, Mitochondrial
  • Macromolecular Substances
  • Guanine
  • NADH Dehydrogenase
  • Adenine