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New evidence from an in vivo study supports the hypothesis that the genetic background of specific tissues can influence expression of a maternally inherited mutation causing blindness. The study was performed in a family of four harbouring point mutation G3460A in mitochondrial DNA (mDNA), which had resulted in Leber's hereditary optic neuropathy (LHON) in the only son at age 18 years. His mother and his twin sisters were unaffected.
The proportion of mutant mDNA in whole blood, platelet and leucocyte fractions, and uroepithelial cells was compared within the family. The three siblings had 100% mutant mDNA in all cell types tested whereas their mother had 56–24%, depending on cell type.
The mutation's known effects in inhibiting activity of the mitochondrial respiratory chain and oxidative phosphorylation were investigated by phosphorus magnetic resonance spectroscopy of the occipital lobe of the brain and of calf muscle. All family members showed abnormalities in measures of oxidative phosphorylation in the brain compared with 35 healthy controls. The measures in calf muscle were within normal range and similar to values in the controls.
The researchers think it unlikely that muscle tissue would differ in its mDNA from the other cell types tested and conclude that tissue specific expression of the mutation is due to differences in the nuclear background.
LHON is the commonest cause of isolated blindness in young men, with the G3460A mutation accounting for up to 19% of cases. A previous cell study suggested that changing the nuclear background might influence biochemical expression of this mutation.