PMC:2495064 / 1152-2713 JSONTXT

{"project":"2_test","denotations":[{"id":"18674747-12805096-2049160","span":{"begin":126,"end":127},"obj":"12805096"},{"id":"18674747-9683591-2049160","span":{"begin":126,"end":127},"obj":"9683591"},{"id":"18674747-10939569-2049160","span":{"begin":126,"end":127},"obj":"10939569"},{"id":"18674747-11261513-2049160","span":{"begin":126,"end":127},"obj":"11261513"},{"id":"18674747-17823937-2049160","span":{"begin":126,"end":127},"obj":"17823937"},{"id":"18674747-17886296-2049160","span":{"begin":126,"end":127},"obj":"17886296"},{"id":"18674747-17222701-2049161","span":{"begin":667,"end":668},"obj":"17222701"},{"id":"18674747-15861210-2049162","span":{"begin":783,"end":784},"obj":"15861210"},{"id":"18674747-15861210-2049163","span":{"begin":1096,"end":1097},"obj":"15861210"},{"id":"18674747-18223651-2049164","span":{"begin":1560,"end":1561},"obj":"18223651"}],"text":"Disease-based epidemiological studies provide estimates of the minimum population prevalence of mtDNA disease as ∼1 in 5000,1–6 but the incidence of new mutations and the frequency of asymptomatic carriers have not been fully established. Fundamental differences between mtDNA inheritance and the Mendelian system mean that de novo mutation rates and carrier frequencies cannot be deduced with a standard Mendelian population-genetic approach. Strict maternal inheritance results in negligible intermolecular recombination apparent at the population level, and the presence of thousands of copies of mtDNA within each diploid mammalian cell adds a further complexity.7 Most pathogenic mtDNA mutations are heteroplasmic, with varying amounts of mutated mtDNA present within each cell.8 Phenotypic expression is ultimately dependent upon the proportion of mutated mtDNA or the amount of wild-type mtDNA within vulnerable tissues. This only leads to a biochemical defect of the respiratory chain when a critical threshold level is exceeded, with the precise amount varying from mutation to mutation.8 In keeping with this, a family with mitochondrial disease usually presents clinically for the first time when an individual inherits a high proportion of mutated mtDNA from a mother who harbors a low level of mutated mtDNA and remains asymptomatic. Such dramatic changes in heteroplasmy can occur in a single generation because of a restriction in the intracellular mtDNA content during embryonic development that is responsible for the mtDNA genetic bottleneck.9"}