CLUSTERING OF CAUCASIAN LEBER HEREDITARY OPTIC NEUROPATHY PATIENTS CONTAINING THE 11778-MUTATION OR 14484-MUTATION ON AN MTDNA LINEAGE

Leber hereditary optic neuropathy (LHON) is a type of blindness caused by mtDNA mutations. Three LHON mtDNA mutations at nucleotide position s 3460, 11778, and 14484 are specific for LHON and account for 90% of worldwide cases and are thus designated as ''primary'' LHON mutations. Fifteen other ''secondary'' LHON mtDNA mutations have been identified , but their pathogenicity is unclear. mtDNA haplotype and phylogenetic analysis of the primary LHON mutations in North American Caucasian pa tients and controls has shown that, unlike the 3460 and 11778 mutation s, which are distributed throughout the European-derived (Caucasian) m tDNA phylogeny, patients containing the 14484 mutation tended to be as sociated with European mtDNA haplotype J. To investigate this apparent clustering, we performed chi(2)-based statistical analyses to compare the distribution of LHON patients on the Caucasian phylogenetic tree. Our results indicate that, unlike the 3460 and 11778 mutations, the 1 4484 mutation was not distributed on the phylogeny in proportion to th e frequencies of the major Caucasian mtDNA haplogroups found in North America. The 14484 mutation was next shown to occur on the haplogroup J background more frequently that expected, consistent with the observ ation that similar to 75% of worldwide 14484-positive LHON patients oc cur in association with haplogroup J. The 11778 mutation also exhibite d a moderate clustering on haplogroup J. These observations were suppo rted by statistical analysis using all available mutation frequencies reported in the literature. This paper thus illustrates the potential importance of genetic background in certain mtDNA-based diseases, spec ulates on a pathogenic role for a subset of LHON secondary mutations a nd their interaction with primary mutations, and provides support for a polygenic model for LHON expression in some cases.