Both authors equally contributed to this work.
1098-1004/asset/HUMU_left.gif?v=1&s=4065e12063da1c0efe3c1a74d4f13c3cd92fba18)
1098-1004/asset/HUMU_right.gif?v=1&s=58026811b6aa5bee5a3d0e0563a705f8b681f34d)
Research Article
You have full text access to this OnlineOpen article
Segregation of mtDNA throughout human embryofetal development: m.3243A>G as a model system†
Article first published online: 22 DEC 2010
DOI: 10.1002/humu.21417
© 2010 Wiley-Liss, Inc.
Additional Information
How to Cite
Monnot, S., Gigarel, N., Samuels, D. C., Burlet, P., Hesters, L., Frydman, N., Frydman, R., Kerbrat, V., Funalot, B., Martinovic, J., Benachi, A., Feingold, J., Munnich, A., Bonnefont, J.-P. and Steffann, J. (2011), Segregation of mtDNA throughout human embryofetal development: m.3243A>G as a model system. Hum. Mutat., 32: 116–125. doi: 10.1002/humu.21417
- †
Communicated by Henrik Dahl
- ‡
Both authors equally contributed to this work.
Publication History
- Issue published online: 22 DEC 2010
- Article first published online: 22 DEC 2010
- Accepted manuscript online: 30 NOV 2010 12:37PM EST
- Manuscript Accepted: 10 NOV 2010
- Manuscript Received: 30 JUN 2010
Funded by
- l'Association Française contre les Myopathies (AFM)
- l'Agence de Biomédecine, l'INSERM
- The European network Mitocircle; l'AFM (to S.M.)
Keywords:
- mitochondria;
- mitochondrial DNA;
- MELAS;
- NARP;
- respiratory chain deficiency;
- embryo;
- preimplantation genetic diagnosis
Abstract
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.