PMC:2495064 / 13715-15415 JSONTXT

{"project":"2_test","denotations":[{"id":"18674747-10939569-2049180","span":{"begin":186,"end":187},"obj":"10939569"},{"id":"18674747-17886296-2049180","span":{"begin":186,"end":187},"obj":"17886296"},{"id":"18674747-17300999-2049181","span":{"begin":340,"end":342},"obj":"17300999"},{"id":"18674747-17886296-2049182","span":{"begin":473,"end":474},"obj":"17886296"},{"id":"18674747-12518276-2049183","span":{"begin":921,"end":923},"obj":"12518276"},{"id":"18674747-9150158-2049184","span":{"begin":1176,"end":1178},"obj":"9150158"},{"id":"18674747-17668373-2049184","span":{"begin":1176,"end":1178},"obj":"17668373"},{"id":"18674747-9239541-2049185","span":{"begin":1342,"end":1344},"obj":"9239541"},{"id":"18674747-14530452-2049186","span":{"begin":1698,"end":1700},"obj":"14530452"}],"text":"Although m.7445A→G, m.8344A→G, m.8993T→G, m.13513G→A, and m.14459G→A were not detected, these mutations are also uncommon in mitochondrial-disease patients from the same UK population.3,6 By contrast, the most common heteroplasmic mutation was m.3243A→G (33%), reaching frequencies similar to that described in one mutation-specific survey.20 m.3243A→G is also the most common heteroplasmic mtDNA mutation in adults with mtDNA disease from the same geographic region (40%).6 Therefore, a high mutation rate provides the likely explanation for the prevalence of m.3243A→G in disease cohorts. By contrast, the carrier frequencies of the three major mutations that cause Leber hereditary optic neuropathy (LHON), m.3460G→A, m.11778G→A, and m.14484T→C, were equal. This differs from the distribution for independent families with LHON in the north of England, where the majority of cases harbor the m.11778G→A mutation (60%).19 All of the asymptomatic m.14484T→C carriers belonged to mtDNA haplogroup J. This is in keeping with the well-established preferential association between haplogroup J and m.14484T→C LHON pedigrees ascertained through clinically affected individuals.24,25 However, the data shown here provide the first direct evidence that this association is not due solely to enhanced clinical expression on J, as previously thought.10 Subhaplogroup analysis by mtDNA D-loop sequencing confirmed the independent recurrence of m.14484T→C in asymptomatic carriers within the population, providing independent evidence that haplogroup J predisposes the mitochondrial genome to mutate at np.14484, possibly through near-neighbor effects as previously described to occur during mtDNA evolution.26"}