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.

Abstract

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.

Identification of Native American Founder mtDNAs Through the Analysis of Complete mtDNA Sequences: Some Caveats

“…It should be noted that the single haplogroup D1 sequence D CA reported by Derbeneva et al (2002) harbours the extremely rare pathogenic mutation at 14459 (associated with both Leber hereditary optic neuropathy and dystonia), and most likely constitutes a correction of the complete mtDNA sequence obtained by Jun et al (1994). The Native American mtDNA sequence na2d from Mishmar et al (2003) is identical to D CA except for the mutation at 13879 (which however is also missing in Fig.…”

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…For example, mutations in MT-ND1 and MT-ND4 can cause Leber hereditary optic neuropathy (LHON), a disease characterized by bilateral, painless central vision loss in early to late adulthood resulting from the specific degeneration of retinal ganglion cells in the optic nerve [40]. However, these same mutations can also be associated with more severe symptoms, including dystonia and short stature [41][42][43].…”

Molecular genetic basis of primary inherited optic neuropathies

“…Other rare primary mutations, including T14596A, C14498T, G13730A, G14459A, C14482G, and A14495G have been identified. [13][14][15] LHON shows variable penetrance and a primary mtDNA mutation is essential but not sufficient to manifest optic neuropathy. So-called 'secondary' mutations may also be involved in the pathogenesis of LHOH but these also occur at a lower prevalence in control populations, where they may represent polymorphisms.…”