The inheritance of pathogenic mitochondrial DNA mutations

Abstract

Mitochondrial DNA mutations cause disease in >1 in 5000 of the population, and approximately 1 in 200 of the population are asymptomatic carriers of a pathogenic mtDNA mutation. Many patients with these pathogenic mtDNA mutations present with a progressive, disabling neurological syndrome that leads to major disability and premature death. There is currently no effective treatment for mitochondrial disorders, placing great emphasis on preventing the transmission of these diseases. An empiric approach can be used to guide genetic counseling for common mtDNA mutations, but many families transmit rare or unique molecular defects. There is therefore a pressing need to develop techniques to prevent transmission based on a solid understanding of the biological mechanisms. Several recent studies have cast new light on the genetics and cell biology of mtDNA inheritance, but these studies have also raised new controversies. Here we compare and contrast these findings and discuss their relevance for the transmission of human mtDNA diseases.

Fig. 1

Models of the mitochondrial genetic bottleneck adapted from . Schematic diagram showing a heteroplasmic fertilized oocyte (top), a model of the mitochondrial genetic bottleneck (middle) and subsequent oocytes (bottom). Blue circles = wild-type mtDNA. Red circles = mutated mtDNA. (a) Prenatal bottleneck. The variance in heteroplasmy levels arises during early embryo and germ-line development due to the random segregation of individual mtDNA molecules before the primary oocyte stage. This model is based on the actual amount of mtDNA measured within single cells as reported in and . Time scale shown on the left in days post coitus (dpc). (b) Postnatal bottleneck. The variance in heteroplasmy levels arises after birth due to the preferential replication of a subpopulation of mtDNA molecules as proposed in .