Segregation of mtDNA throughout human embryofetal development: m.3243A>G as a model system.
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.
Université Paris-Descartes, Unité INSERM U, Hopital Necker-Enfants Malades, France.
Sophie
S
Monnot
Nadine
N
Gigarel
David C
DC
Samuels
Philippe
P
Burlet
Laetitia
L
Hesters
Nelly
N
Frydman
René
R
Frydman
Violaine
V
Kerbrat
Benoit
B
Funalot
Jelena
J
Martinovic
Alexandra
A
Benachi
Josué
J
Feingold
Arnold
A
Munnich
Jean-Paul
JP
Bonnefont
Julie
J
Steffann
D004272:DNA, Mitochondrial / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D047109:Fetal Development / Q000235:genetics; D018628:Gene Dosage; D006801:Humans; D017241:MELAS Syndrome / Q000196:embryology / Q000235:genetics; D008957:Models, Genetic; D009154:Mutation; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods / Q000706:statistics & numerical data
D004272:DNA, Mitochondrial