Segregation pattern and biochemical effect of the G3460A mtDNA mutation in 27 members of LHON family

Abstract 

Inheritance and expression of mitochondrial DNA (mtDNA) mutations are crucial for the pathogenesis of Leber hereditary optic neuropathy (LHON). We have investigated the segregation and functional consequences of G3460A mtDNA mutation in 27 members of a three-generation family with LHON syndrome. Specific activity of respiratory chain complex I in platelets was reduced in average to 56%, but no direct correlation between the mutation load and its biochemical expression was found. Heteroplasmy in blood, platelets and hair follicles varied from 7% to 100%. Segregation pattern exhibited tissue specificity and influence of different nuclear backgrounds in four branches of the pedigree. Longitudinal analysis revealed a significant (p=0.02) decrease in blood mutation load. Although enzyme assay showed reduction of complex I activity, our results give additional support to the hypothesis that expression of LHON mutation depends on complex nuclear–mitochondrial interaction.

Keywords:  LHON, Complex I (NADH dehydrogenase), Mitochondrial DNA, Segregation, Nuclear background, G3460A mutation

Abbreviations:  LHON, Leber's hereditary optic neuropathy, mtDNA, mitochondrial DNA, OXPHOS, oxidative phosphorylation, CS, citrate synthase