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Co-segregation and heteroplasmy of two coding-region mtDNA mutations within a matrilineal pedigree

Lookup NU author(s): Sharon Foster, Emeritus Professor Doug Turnbull, Professor Patrick Chinnery


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The ENG1 Leber's hereditary optic neuropathy (LHON) family spans six generations and comprises more than 90 maternally related individuals. In this pedigree, the G:A LHON mutation at nucleotide position 11778 shows a complex pattern of segregation in which it is homoplasmic mutant in two branches, homoplasmic wildtype in another, and heteroplasmic in a fourth branch. In addition, there is co-segregation of the 11778 mutant allele and of a G:A silent polymorphism at nucleotide position 5471 in 18 of 19 family members. This co-segregation indicates that the two substitutions arose either simultaneously, or nearly so, in the same "founder" mtDNA molecule. However, the highly divergent mitochondrial allele ratios in the one family member suggest that there has been a complex origin and segregation "history" of these two substitutions. Taking all of the results into consideration, the evidence supports sequential single mutations at sites 5471 and 11778, in close temporal proximity, with subsequent segregation of the intermediate mutational genotype to high levels in one branch of the ENG1 LHON family. In other branches, either the double wildtype or double mutant genotype has become essentially homoplasmic. © Springer-Verlag 2004.

Publication metadata

Author(s): Howell N, Kubacka I, Keers SM, Turnbull DM, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Human Genetics

Year: 2005

Volume: 116

Issue: 1-2

Pages: 28-32

ISSN (print): 0340-6717

ISSN (electronic): 1432-1203

Publisher: Springer


DOI: 10.1007/s00439-004-1203-x

PubMed id: 15599765


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Funder referenceFunder name
074454Wellcome Trust