Detection of Mitochondrial DNA Mutations Associated with Leber Hereditary Optic Neuropathy

Human genetic disease linked to mitochondrial DNA (mtDNA), the other genome in our cells, was first recognized in 1988 (1 ,2 ). Mitochondrial genetics has certain unique features (reviewed in ref. 3 ): 1) Maternal inheritance: Mitochondria are maternally inherited and therefore mtDNA mutations are transmitted through maternal lineage. 2) Heteroplasmy: The presence mutant mtDNA in a population of normal molecules is termed heteroplasmy. The proportion of mutant molecules may be different in different tissues and can change with cycles of cell division. 3) Replicative segregation: Mitochondria are partitioned along with the cytoplasm during cell division. The distribution of mutant and normal molecules in the daughter cells of heteroplasmic cell may be unequal. In the course of development and differentiation, different parts of the body may have different proportion of mutant molecules. 4) Threshold effect: The percentage of mutant mtDNA molecules and the energetic needs of the tissue influence the penetrance of mutations. The effect of mtDNA mutations may become evident when either the number of mutant molecules or the deleterious effect exceeds a threshold. 5) High mutation rate: The mtDNA has a much higher mutation rate than nuclear DNA. This results in the recurrence of some mutations in different haplotype backgrounds. The high mutation rate also contributes to polymorphisms.