Leber’s hereditary optic neuropathy is associated with mitochondrial ND1 T3394C mutation

Abstract

We report here the clinical, genetic and molecular characterization of four Chinese families with Leber's hereditary optic neuropathy (LHON). There were variable severity and age-of-onset in visual impairment among these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of complete mitochondrial genomes in these pedigrees showed the homoplasmic T3394C (Y30H) mutation, which localized at a highly conserved tyrosine at position 30 of ND1, and distinct sets of mtDNA polymorphisms belonging to haplogroups D4b and M9a. The occurrence of T3394C mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. However, there was the absence of functionally significant mtDNA mutations in these four Chinese pedigrees carrying the T3394C mutation. Therefore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of the LHON-associated T3394C mutation.

Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans

“…Although the 3394C variant on macrohaplogroup N B4 and F1 mtDNAs was associated with reduced complex I activity, the 3394C variant on the macrohaplogroup M mtDNA M9 had the highest complex I activity. Hence, the functional benefit of the 3394C allele is only manifested in the context of macrohaplogroup M. Still, haplogroup background is insufficient to explain all of the phenotypic consequences of the 3394C variant, because the 3394C variant on the M9 haplogroup has been associated with LHON in low-altitude Asian populations (24,25). Thus, environment must also modulate the phenotypic consequence of the 3394C variant.…”

“…The environmental factors that render the 3394C variant on M9 deleterious at low altitude remain unknown (25), although reduced oxygen tension is one likely factor. Physiological alterations have been observed in high-altitude Tibetan, Peruvian Andean Native Americans, and India subcontinent populations (40,41), which may be the result of changes in mitochondrial physiology (42,43).…”

“…However, in four other Chinese LHON patients the 3394C variant was the only potentially pathogenic mutation, occurring on haplogroups D4b and M9a (25). Therefore, the 3394C variant lies at the interface between a pathogenic and a polymorphic variant and permits addressing the question: What level of mitochondrial complex I defect is necessary to produce LHON?…”

A mitochondrial bioenergetic etiology of disease

“…When arising on macrohaplogroup N mt DNAs, this variant is associated with increased penetrance of the milder primary LHON mtDNA mutations (18,19). Yet when this same ND1 T3394C (Y30H) variant arose on macrohaplogroup M mtDNAs, it became enriched in high-altitude Tibetans.…”

Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in Evolution and Disease

“…This is particularly clearly demonstrated for the mtDNA variant in ND1 at nt 3394C, which causes amino acid substitution Y30H (Ji et al 2012). When this variant arises on macrohaplogroup N mtDNAs, it reduces mitochondrial complex I activity by 15% -28% and markedly increases the penetrance of the milder LHON mutations (Brown et al 1995;Liang et al 2009). However, if the mutation arises on a macrohaplogroup M mtDNA and this mtDNA resides in high altitude, then this same variant is associated with maximum complex I activity and adaptation to high altitude (Ji et al 2012).…”