Author(s): Chinnery PF, Zwijnenburg PJG, Walker M, Howell N, Taylor RW, Lightowlers RN, Bindoff L, Turnbull DM
Abstract: Heteroplasmic mitochondrial DNA (mtDNA) defects are an important cause of inherited human disease. On a cellular level, the percentage of mutant mtDNA is the principal factor behind the expression of the genetic defect. Marked variation in the level of mutant mtDNA among tissues is thought to be responsible for the diverse clinical phenotypes associated with the same pathogenic mtDNA mutation. This study was designed to determine whether the percentage level of a pathogenic mtDNA molecule is determined by a purely random process. The tissue distribution of the A3243G MELAS point mutation was analyzed in five individuals who were members of a family with maternally inherited diabetes and deafness. The level of mutant mtDNA was measured in four tissues in three individuals and three tissues in two individuals. The highest level of mutant mtDNA occurred in skeletal muscle, followed by hair follicles, and then buccal mucosa, with the lowest levels in blood (leucocyte/platelet fraction). The probability of observing any strict hierarchy in family is 4.82 × 10−5. These results indicate that the distribution of the A3243G mutation is not solely determined by random processes.
Keywords: mitochondrial disease;mitochondrial DNA, mitochondrial DNA segregation;heteroplasmy;MELAS