PHYLOGENETIC ANALYSIS OF LEBERS HEREDITARY OPTIC NEUROPATHY MITOCHONDRIAL DNAS INDICATES MULTIPLE INDEPENDENT OCCURRENCES OF THE COMMON MUTATIONS

The mitochondrial DNAs (mtDNA) from 17 Caucasian 11778-positive and 30 Caucasian 11778-negative Leber's hereditary optic neuropathy (LHON) p atients were PCR amplified and subjected to high resolution restrictio n endonuclease analysis. Concurrently, all patient mtDNAs were screene d for the common primary LHON mtDNA mutations at nucleotide pairs (nps ) 3460, 11778, and 14484, the ambiguous intermediate-risk LHON mtDNA m utations at nps 5244 and 15257, and the secondary LHON mtDNA mutations at nps 3394, 4216, 4917, 7444, 13708, and 15812. Phylogenetic analysi s was performed using mtDNA haplotype data from the 47 LHON patients a nd 175 non-LHON Caucasian controls. The superimposition of the LHON mu tation screening results upon the Caucasian mtDNA phylogeny revealed ( 1) 35 different LHON haplotypes, (2) that all three common primary mut ations have occurred multiple times in Caucasians, (3) that while recu rrent mutation is common for the primary mutations, secondary mutation s tend to be lineage-specific, (4) that the np 15257 mutation was conf ined to a single mtDNA lineage but may be etiologically important in s ome LHON cases since it was found in a LHON pedigree which lacked a co mmon primary mutation; complete sequence analysis of the proband mtDNA revealed only a single other candidate missense mutation (at np 10663 of the ND4L gene) of uncertain pathological significance; and (5) tha t the np 14484 mutation may be less pathogenic than either the np 3460 or np 11778 mutations, as this mutation most commonly occurred on a s ingle mtDNA lineage and almost always in association with secondary LH ON mutations. A phylogenetic approach to this genetically heterogeneou s disease has thus provided key genetic data bearing on the relative p athogenicity of the LHON-associated mtDNA mutations. (C) 1995 Wiley-Li ss, Inc.