Detection of the mtDNA 14484 mutation on an African-specific haplotype: implications about its role in causing Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally transmitted disease whose primary clinical manifestation is acute or subacute bilateral loss of central vision leading to central scotoma and blindness. To date, LHON has been associated with 18 mtDNA missense mutations, even though, for many of these mutations, it remains unclear whether they cause the disease, contribute to the pathology, or are nonpathogenic mtDNA polymorphisms. On the basis of numerous criteria, which include the specificity for LHON, the frequency in the general population, and the penetrance within affected pedigrees, the detection of associated defects in the respiratory chain, mutations at three nucleotide positions (nps), 11778 (G arrow right A), 3460 (G arrow right A), and 14484 (T arrow right C); have been classified as high-risk and primary LHON mutations. Overall, these three mutations encompass greater than or equal to 90% of the LHON cases. From an evolutionary point of view, there is a major criterion that helps to distinguish severe mtDNA mutations from low-risk mtDNA mutations and/or population-specific polymorphisms. High-risk mutations, i.e., mutations that do not require additional mtDNA mutations to cause the phenotype and have a high degree of penetrance, are under a relatively strong selective pressure. Therefore, they are likely to be lost, together with the mtDNAs on which they occurred, within few generations from their occurrence. However, these mutations are continuously generated in the general population and continuously generate new affected pedigrees. Since the new mutational events occur randomly, severe mtDNA mutations are expected to be found on heterogeneous mtDNA backgrounds and in all human populations. On the contrary, low-risk mutations with lower penetrance are under a milder selective pressure and, similar to neutral mutations, can be transmitted for numerous generations. Transmission through numerous generations makes it possible for a mutation generated by a single mutational event to be transmitted by descent to numerous pedigrees, which would appear to be unrelated even though they share a female ancestor. If most of the pedigrees affected are thus related, these mutations may appear as population specific.