Nonrandom tissue distribution of mutant mtDNA

Heteroplasmic mitochondrial DNA (mtDNA) defects are an important cause of i nherited human disease. On a cellular level, the percentage of mutant mtDNA is the principal factor behind the expression of the genetic defect, Marke d variation in the level of mutant mtDNA among tissues is thought to be res ponsible for the diverse clinical phenotypes associated with the same patho genic mtDNA mutation. This study was designed to determine whether the perc entage level of a pathogenic mtDNA molecule is determined by a purely rando m process, The tissue distribution of the A3243G MELAS point mutation was a nalyzed in five individuals who were members of a family with maternally in herited diabetes and deafness, The level of mutant mtDNA was measured in fo ur tissues in three individuals and three tissues in two individuals. The h ighest level of mutant mtDNA occurred in skeletal muscle, followed by hair follicles, and then buccal mucosa, with the lowest levels in blood (leucocy te/platelet fraction). The probability of observing any strict hierarchy in family is 4.82 x 10(-5), These results indicate that the distribution of t he A3243G mutation is not solely determined by random processes. (C) 1999 W iley-Liss, Inc.