Longitudinal analysis of the segregation of mtDNA mutations in heteroplasmic individuals

The mutation load of the pathogenic LHON (Leber hereditary optic neuropathy ) mtDNA mutation at nucleotide 3460 has been followed over time in the WBC/ platelet fraction from members of a matrilineal pedigree. Longitudinal anal ysis over a sampling period of five to six years indicates that, in all fiv e heteroplasmic family members, the mutation load decreases at a mean overa ll rate of approximately 1% per year. There was no change in mutation load in homoplasmic wildtype or in homoplasmic mutant individuals. For the purpo ses of comparison, a longitudinal analysis of a silent mtDNA polymorphism a t nucleotide 14560 was also carried out for members of a second matrilineal pedigree. In contrast to the results for the pathogenic mtDNA mutation, th ere was no change in the proportion of the silent polymorphism in the WBC/p latelet fraction of four family members over a period of seven years. These results indicate that the pathogenic 3460 LHON mutation segregates under n egative selection in these cell populations. One possible mechanism through which selection may operate is that, in heteroplasmic individuals, the hem atopoietic stem cells are generally homoplasmic, either for the wildtype or for the mutant allele. The homoplasmic mutant stem cells, because of their mitochondrial respiratory chain defect, produce fewer mature WBCs and plat elets over time than do the wildtype stem cells. Alternatively, the stem ce lls may be heteroplasmic and selection may act to favor proliferation of mi tochondria with lower levels of the pathogenic mutation in the WBC/platelet cell populations. (C) 2000 Elsevier Science BN. All rights reserved.