Leber's Hereditary Optic Neuropathy-Specific Mutation m.11778G>A Exists on Diverse Mitochondrial Haplogroups in India

Leber's hereditary optic neuropathy (LHON; OMIM 535000) is one of the most common maternally inherited mitochondrial disorders. Three mitochondrial DNA point mutations-m.3460G>A (MT-ND1), m.11778G>A (MT-ND4), and m.14484T>C (MT-ND6)-account for the majority of reported LHON cases. Only approximately 50% of males and approximately 10% of females carrying these mutations develop optic neuropathy and blindness. Additional factors, such as mtDNA/nuclear genetic background and environmental modifiers, are likely to contribute toward the observed incomplete penetrance and gender bias. We aimed to investigate whether mtDNA haplogroup influences LHON clinical expression in Indian patients harboring the m.11778G>A mutation.

Detailed clinical assessment and complete mitochondrial genome sequencing was undertaken in 64 LHON families harboring the m.11778G>A mutation. Mitochondrial haplogroup was assigned based on evolutionarily conserved mtDNA variations.

A total of 543 individuals (295 male, 248 female) from 64 unrelated families harboring the m.11778G>A mutation were recruited to the study. The overall disease penetrance was 27.07% (146 of 543) and higher in males (37.9%; 112 of 295) than females (13.7%; 34 of 248). The mtDNA haplogroup analysis revealed that all affected probands belonged to different mtDNA haplogroups. No association between the m.11778G>A mutation and the background mtDNA haplogroup was detected.

The first detailed study of Indian LHON patients confirm that the m.11778G>A-related LHON in India coexists with multiple different mtDNA haplogroups, unlike the preferential association of west Eurasian haplogroup J and the reported increased clinical penetrance with the J2 subhaplogroup. However, we observed variable penetrance of LHON in different Indian mtDNA haplogroup backgrounds, indicating their possible influence on clinical expression. These data suggest that a similar heterogeneity, resulting from the mtDNA haplogroup, might also exist in other mitochondrial diseases among Indian populations.