Mitochondrial haplotypes have been thought to influence the clinical expression of LHON-associated primary mtDNA mutations. In European families, the risk of optic neuropathy increases when the G11778A and T14484C mutations are present in haplogroup J
13,15,47,48 and when the G3460A mutation occurs in haplogroup K.
13 On the other hand, the risk of visual failure reduces when the G11778A mutation is present in haplogroup H.
13 In the Chinese families carrying the G11778A mutation, haplogroup M7b1′2 significantly increases the risk of optic neuropathy, whereas haplogroup M8a has a protective effect.
16 Furthermore, secondary LHON mutations such as
ND1 T4216C and
ND5 G13708A may increase the penetrance and expressivity of LHON associated with the primary LHON G11778A and T14484C mutations.
8,14,15,49 In addition, the G7444A mutation in the
CO1 and
tRNASer(UCN) genes has also been thought to influence the penetrance and phenotypic occurrence of visual loss associated with the primary LHON mutations.
8 Most recently, we have shown that the
ND4 G11696A, tRNA
Met A4435G, and tRNA
Thr A15951G mutations increase the penetrance and expressivity of visual loss in Chinese families carrying the G11778A mutation.
19–21 In these two Chinese families with the mutation, there were distinct sets of sequence variations in their mitochondrial genomes belonging to haplogroup M1 and M10a, respectively. As shown in
Table 2, mtDNAs of the other 15 Chinese pedigrees carrying the G11778A mutation belong to haplogroups B4a, B5, C, D4, D5, D4, F1, M7b, M8a, M10a, and N9a.
12,18–21 This finding suggests that the G11778A mutation, similar to the mutation in Caucasian and Japanese families,
8,10,13,15,17 occurs sporadically and that it multiplies through the evolution of the mtDNA in the Chinese population. Of these mtDNA variants in two Chinese families, the L175F variant in
CO3; the I58V variant in the
ND6; and the I189V, L292R, and S297A variants in
CYTB are located at highly conserved residues of polypeptides. The highly evolutionary conservation of these variants makes them likely to be functionally significant in terms of mitochondrial physiology.
31 These notions further supported recent observations that the ND6 I58V variant is involved in LHON in Chinese families,
32 the
CO3 L175F variant is associated with LHON in Thai families,
33 and the
CYTB I189V variant is found in hypertensive individuals.
34 Thus, these mitochondrial haplogroup-specific variants, together with nuclear modifier genes and epigenetic and environmental factors, may contribute to the phenotypic manifestation of LHON-associated G11778A mutation in these two Chinese pedigrees. The understanding of these modifier factors is important for the elucidation of the pathophysiology of LHON and to open avenues for therapeutic interventions for this disorder.