title: Poor correlations in the levels of pathogenic mitochondrial DNA mutations in polar bodies versus oocytes and blastomeres in humans.
abstract: Because the mtDNA amount remains stable in the early embryo until uterine implantation, early human development is completely dependent on the mtDNA pool of the mature oocyte. Both quantitative and qualitative mtDNA defects therefore may negatively impact oocyte competence or early embryonic development. However, nothing is known about segregation of mutant and wild-type mtDNA molecules during human meiosis. To investigate this point, we compared the mutant levels in 51 first polar bodies (PBs) and their counterpart (oocytes, blastomeres, or whole embryos), at risk of having (1) the "MELAS" m.3243A>G mutation in MT-TL1 (n = 30), (2) the "MERRF" m.8344A>G mutation in MT-TK (n = 15), and (3) the m.9185T>G mutation located in MT-ATP6 (n = 6). Seven out of 51 of the PBs were mutation free and had homoplasmic wild-type counterparts. In the heteroplasmic PBs, measurement of the mutant load was a rough estimate of the counterpart mutation level (R(2) = 0.52), and high mutant-load differentials between the two populations were occasionally observed (ranging from -34% to +34%). The mutant-load differentials between the PB and its counterpart were higher in highly mutated PBs, suggestive of a selection process acting against highly mutated cells during gametogenesis or early embryonic development. Finally, individual discrepancies in mutant loads between PBs and their counterparts make PB-based preconception diagnosis unreliable for the prevention of mtDNA disorder transmission. Such differences were not observed in animal models, and they emphasize the need to conduct thorough studies on mtDNA segregation in humans.
authors.affiliation: Université Paris-Descartes, Faculté de Médecine, Unité INSERM U781, Service de Génétique Médicale, Hôpital Necker-Enfants Malades (Assistance Publique-Hôpitaux de Paris), 149 rue de Sèvres, 75743 Paris Cedex 15, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Gigarel
authors.forename: Laetitia
authors.initials: L
authors.lastname: Hesters
authors.forename: David C
authors.initials: DC
authors.lastname: Samuels
authors.forename: Sophie
authors.initials: S
authors.lastname: Monnot
authors.forename: Philippe
authors.initials: P
authors.lastname: Burlet
authors.forename: Violaine
authors.initials: V
authors.lastname: Kerbrat
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lamazou
authors.forename: Alexandra
authors.initials: A
authors.lastname: Benachi
authors.forename: René
authors.initials: R
authors.lastname: Frydman
authors.forename: Josué
authors.initials: J
authors.lastname: Feingold
authors.forename: Agnes
authors.initials: A
authors.lastname: Rotig
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Bonnefont
authors.forename: Nelly
authors.initials: N
authors.lastname: Frydman
authors.forename: Julie
authors.initials: J
authors.lastname: Steffann
mesh_terms: D001757:Blastomeres / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism*; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D006801:Humans; D017241:MELAS Syndrome / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D017243:MERRF Syndrome / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008297:Male; D008540:Meiosis / Q000235:genetics; D009154:Mutation; D009865:Oocytes / Q000378:metabolism*; D009866:Oogenesis / Q000235:genetics; D011247:Pregnancy; D019836:Preimplantation Diagnosis
chemical_list: D004272:DNA, Mitochondrial