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Segregation of mtDNA throughout human embryofetal development: m.3243A>G as a model system
Author(s) -
Monnot Sophie,
Gigarel Nadine,
Samuels David C.,
Burlet Philippe,
Hesters Laetitia,
Frydman Nelly,
Frydman René,
Kerbrat Violaine,
Funalot Benoit,
Martinovic Jelena,
Benachi Alexandra,
Feingold Josué,
Munnich Arnold,
Bonnefont JeanPaul,
Steffann Julie
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21417
Subject(s) - heteroplasmy , biology , mitochondrial dna , oogenesis , genetics , mitochondrial disease , melas syndrome , mutation , reproductive technology , embryo , gene , embryogenesis , mitochondrial myopathy
Mitochondrial DNA (mtDNA) mutations cause a wide range of serious diseases with high transmission risk and maternal inheritance. Tissue heterogeneity of the heteroplasmy rate (“mutant load”) accounts for the wide phenotypic spectrum observed in carriers. Owing to the absence of therapy, couples at risk to transmit such disorders commonly ask for prenatal (PND) or preimplantation diagnosis (PGD). The lack of data regarding heteroplasmy distribution throughout intrauterine development, however, hampers the implementation of such procedures. We tracked the segregation of the m.3243A>G mutation ( MT‐TL1 gene) responsible for the MELAS syndrome in the developing embryo/fetus, using tissues and cells from eight carrier females, their 38 embryos and 12 fetuses. Mutant mtDNA segregation was found to be governed by random genetic drift, during oogenesis and somatic tissue development. The size of the bottleneck operating for m.3243A>G during oogenesis was shown to be individual‐dependent. Comparison with data we achieved for the m.8993T>G mutation ( MT‐ATP6 gene), responsible for the NARP/Leigh syndrome, indicates that these mutations differentially influence mtDNA segregation during oogenesis, while their impact is similar in developing somatic tissues. These data have major consequences for PND and PGD procedures in mtDNA inherited disorders. Hum Mutat 32:116–125, 2011. © 2010 Wiley‐Liss, Inc.