Mitochondrial DNA haplogroup distribution within Leber hereditary optic neuropathy pedigrees

Abstract

Leber hereditary optic neuropathy (LHON; OMIM #535000) is a mitochondrial genetic disease that causes blindness in young adults, with an estimated minimum prevalence of 3.2 per 100 000 in the north east of England.1 It classically presents as bilateral subacute loss of central vision due to the focal neurodegeneration of the retinal ganglion cell layer. Over 95% of cases are principally due to one of three “primary” mtDNA point mutations: 3460G→A, 11778G→A, and 14484T→C, all of which involve genes that encode complex I subunits of the mitochondrial respiratory chain. However, less than ~50% of male and ~10% of female LHON carriers will develop the optic neuropathy.2,3 This marked incomplete penetrance and gender bias clearly indicates that additional genetic and/or environmental factors are required for the phenotypic expression of the pathogenic mtDNA mutations in LHON. However, these secondary factors remain poorly defined at the present time. There has recently been considerable interest in the possible role of the mtDNA background on the phenotypic expression of mitochondrial genetic disorders. The hypothesis is that on their own, some polymorphisms are selectively “neutral” but that in specific combinations, they act in a synergistic, deleterious manner with established pathogenic mtDNA mutations to increase the risk of disease expression or to produce a more severe clinical outcome.4 The following nucleotide substitutions are found at a higher frequency in LHON patients relative to controls:5–7 4216T→C, 4917A→G, 9804G→A, 9438G→A, 13708G→A, 15257G→A, and 15812G→A. Phylogenetic analysis has shown that 4216T→C, 13708G→A, 15257G→A, and 15812G→A all cluster on a specific mtDNA background, haplogroup J, which is one of the nine haplogroups that define populations of European ancestry.8,9 Several studies have subsequently found that LHON pedigrees that harbour the 11778G→A and 14484T→C mutations are apparently not randomly distributed along the phylogenetic tree, but …