Segregation of mtDNA Throughout Human Embryofetal Development: m.3243A>G as a Model System

Sophie Monnot (1, 2, 3) , Nadine Gigarel (3) , David C Samuels (4) , Philippe Burlet (3) , Laetitia Hesters (5) , Nelly Frydman (5) , René Frydman (5) , Violaine Kerbrat (5) , Benoît Funalot (3) , Jéléna Martinovic (6) , Alexandra Benachi (7) , Josué Feingold (3) , Arnold Munnich (1, 2, 3) , Jean-Paul Bonnefont (1, 2, 3) , Julie Steffann (1, 2, 3)

1 UPD5 - Université Paris Descartes - Paris 5
2 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
3 Service de Génétique Médicale [CHU Necker]
4 Molecular Physiology and Biophysics
5 Service de gynécologie-obstétrique, médecine de la reproduction [Béclère]
6 Genetics
7 Service d'obstétrique

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 intra uterine 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 8 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.

Mots clés: Life Sciences

Sophie Monnot, Nadine Gigarel, David C Samuels, Philippe Burlet, Laetitia Hesters, et al.. Segregation of mtDNA Throughout Human Embryofetal Development: m.3243A>G as a Model System. Human Mutation, 2010, 32 (1), pp.116. ⟨10.1002/humu.21417⟩. ⟨hal-00602304⟩