Phylogenetic assessment of the mitochondrial DNA displacement loop haplotype in Japanese patients with Leber's hereditary optic neuropathy harboring the mitochondrial DNA G11778A mutation.

To investigate the anthropological background and the association of mitochondrial DNA (mtDNA) haplotype with the disease phenotype, the nucleotide sequence in the hypervariable segment of the displacement loop (D-loop) region of mtDNA was determined in Japanese patients with Leber's hereditary optic neuropathy (LHON) harboring the G11778A mutation. Genetic polymorphism of mtDNA was examined in 36 unrelated Japanese LHON patients who presented with bilateral optic nerve disease and had the mtDNA G11778A mutation. DNA was extracted from the peripheral blood after having obtained informed consent. The nucleotide sequence of the D-loop region (np 16,002-16,490) was directly determined. The intergenic deletion of the COII/tRNA(Lys) gene of mtDNA was also examined. From the data set of nucleotide alignments, the phylogeny of the mtDNA sequence and phenotypic diversity within the examined population were evaluated. One-base polymorphism was present at 37 different sites. The estimated value of nucleotide diversity was 0.69%. D-loop sequences were classified into 13 monophyletic clusters (CA to CM). There was not any definite ancestral haplotype of the D-loop sequence in the examined LHON population. Thus, the mutational event of G11778A appears to be independent of the evolutionary course in the D-loop haplotype. Patients with a CD plus CH cluster had a significantly older age at onset (p = 0.006), and had a family history being significantly lower as compared with patients with other clusters (p = 0.05). The mtDNA D-loop haplotype characterized by the presence of T16362C or C16290T, lacking G16129A and G16390A, may be a risk for older age at onset and other unusual clinical features in Japanese LHON patients with the G11778A mutation.