Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them

Abstract

Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy—the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk (i.e., those having low mutant mtDNA load) can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders.

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

“…Our results support a severe germline bottleneck-with effective size of only 30-35-and are particularly striking given ∼100,000 mtDNAs in mature human oocytes (12). Our findings corroborate strong shifts in heteroplasmy frequency observed in Holstein cows (43,44) but are more robust because they are based on more accurate estimation of MAF changes at many sites, in two tissues, and for a large number of transmissions from multiple families.…”

“…Considering heteroplasmy-containing quartets (Dataset S1, Table S3), we used the presence of heteroplasmy with MAF ≥1% in at least one sample from a family as a "prior" to support the existence of heteroplasmy at the same position for other samples of the same family if their MAF was ≥0.2% (greater than or equal to twice the value of the allowed sequencing quality error of 0.1%-Phred score 30). We classified 98 quartets into five categories (Table 3 and Dataset S1, Table S3) based on whether heteroplasmies were present in (i) both tissues of a mother and both tissues of her child (category "all," which included dramatic shifts in allele frequency from mother to child, suggesting the germ-line bottleneck); (ii) both tissues of a mother, but absent from both tissues of her child (category "mother," suggesting loss of a variant in the child owing to the germ-line bottleneck); (iii) both tissues of a child, but absent from both tissues of a mother (category "child" with candidate germ-line de novo mutations); (iv) both tissues of a mother and one tissue of a child, or in one tissue of a mother and both tissues of a child (category "somatic loss," suggestive of a change in MAF in tissues owing to mitotic segregation) (12); and (v) one tissue of one individual of a family (category "somatic gain" with candidate somatic de novo mutations).…”

“…Genetic drift theory predicts that a small bottleneck size will result in drastic shifts in heteroplasmy levels from a mother to her child, potentially reaching nondisease levels or levels with higher disease severity. After fertilization, mtDNA variants are distributed among cells owing to mitotic segregation-the random partitioning of mitochondria during cell divisions (12). We also lack an accurate estimate of the germ-line mtDNA mutation rate in humans, with pedigree and phylogenetic studies producing conflicting results (13,14).…”

Metabolism of the preimplantation embryo: 40 years on

“…Mitochondrial events in early embryos are likely to offer rich pickings for researchers, with much to be done; for example, the elegant study of Lane & Gardner (2005) on the mitochondrial malate-aspartate shuttle is one of few such investigations, and the special properties of mitochondrial DNA (mtDNA; Poulton et al 2010, St John et al 2010 provide an interesting backdrop. Thus, in an intriguing hypothesis that unites genetics and metabolism, Bendich (2010) has proposed that germ cells are maintained in a metabolically quiet state in order to limit mitochondrial activity and ROS formation and protect mtDNA, which is extremely unstable and has limited repair capacity, from degradation.…”

Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment

“…Most of individuals with these mutations do not have any clinical manifestations [Schaefer et al, 2008;Spinazzola, 2011]. Indeed, only 1 in 5,000 individuals is estimated to phenotypically express clinical manifestations of these mutations [Skladal et al, 2003;Poulton et al, 2010]. Aberrations in mtDNA include point mutations and deletions and, in rare cases, duplications [Mancuso et al, 2004].…”