Mitochondrial DNA polymorphism in disease: a possible contributor to respiratory dysfunction

Abstract

Intergenomic variation in the human mitochondrial genome was examined in 27 mtDNA sequences using a pairwise analysis technique. Analysis of 16 of these mtDNA sequences from patients with mitochondrial cystopathies Indicated a wide range between different mitochondrial genes in the degree of nucleotide variation from the standard Cambridge sequence. Mean complex I ploymorphic frequenceles in cytopathic (CPEO, MERRF, MELAS and LHON collecstively) patients and in LHON pastients differed significantly from controls (P≤0.05, t).Total mean sequence divergence (mean number of diverging nucleotides between two sequences per 100 bp) over the entiere mtDNA coding region was 0.21% for cytropathies (n = 16) as opposed to 0.18% for a control group (n = 4). Within the cytopathy group, the greatest pairwise divergence was observed in ND3 and ND6 subunits of complex i (0.46 and 0.70% respectively) and the magnitude of specific gene divergences differed considerably from those observed for the corresponding genes in the control population. The extent to which the Increassed vasriation in ND3 and ND6 is a general phenomenon applicable to all subjects rather than a finding specific to cytopathies cannot be stated with certainty given the small congtrol group. Regardless as to which of these suggestions is correct, the possibility exists that increased nucleotide variastion in certain mitochondrial ND subunits may contribute to respiratory inefficiency through a cumulative effect of a series of polymorphisms of minor Individual mutagenic potential.