HAPLOTYPE AND PHYLOGENETIC ANALYSES SUGGEST THAT ONE EUROPEAN-SPECIFIC MTDNA BACKGROUND PLAYS A ROLE IN THE EXPRESSION OF LEBER HEREDITARY OPTIC NEUROPATHY BY INCREASING THE PENETRANCE OF THE PRIMARY MUTATION-11778 AND MUTATION-14484

mtDNAs from 37 Italian subjects affected by Leber hereditary optic neu ropathy (LHON) (28 were 11778 positive, 7 were 3460 positive, and 2 we re 14484 positive) and from 99 Italian controls were screened for most of the mutations that currently are associated with LHON. High-resolu tion restriction-endonuclease analysis also was performed on all subje cts, in order to define the phylogenetic relationships between the mtD NA haplotypes and the LHON mutations observed in patients and in contr ols. This analysis shows that the putative secondary/intermediate LHON mutations 4216, 4917, 13708, 15257, and 15812 are ancient polymorphis ms, are associated in specific combinations, and define two common Cau casoid-specific haplotype groupings (haplogroups J and T). On the cont rary, the same analysis shows that the primary mutations 11778, 3460, and 14484 are recent and are due to multiple mutational events. Howeve r, phylogenetic analysis also reveals a different evolutionary pattern for the three primary mutations. The 3460 mutations are distributed r andomly along the phylogenetic trees, without any preferential associa tion with the nine haplogroups (H, I, J, K, T, U, V, W, and X) that ch aracterize European populations, whereas the 11778 and 14484 mutations show a strong preferential association with haplogroup J. This findin g suggests that one ancient combination of haplogroup J-specific mutat ions increases both the penetrance of the two primary mutations 11778 and 14484 and the risk of disease expression.