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

被引：87

作者：

Monnot, Sophie ^{[1
,2
]}

Gigarel, Nadine ^{[1
,2
]}

Samuels, David C. ^{[3
]}

Burlet, Philippe ^{[1
,2
]}

Hesters, Laetitia ^{[4
]}

Frydman, Nelly ^{[4
]}

Frydman, Rene ^{[4
]}

Kerbrat, Violaine ^{[4
]}

Funalot, Benoit ^{[1
,2
]}

Martinovic, Jelena ^{[5
]}

Benachi, Alexandra

Feingold, Josue ^{[1
,2
]}

Munnich, Arnold ^{[1
,2
]}

Bonnefont, Jean-Paul ^{[1
,2
]}

Steffann, Julie ^{[1
,2
]}

机构：

[1] Hop Necker Enfants Malad, Assistance Publ Hop Paris, Paris, France

[2] Univ Paris 05, Unite INSERM U781, Paris, France

[3] Vanderbilt Univ, Dept Mol Physiol & Biophys, Med Ctr, Ctr Human Genet Res, Nashville, TN 37232 USA

[4] Hop Antoine Beclere, Assistance Publ Hop Paris, Serv Gynecol & Med Reprod, Clamart, France

[5] Hop Necker Enfants Malad, Assistance Publ Hop Paris, Serv Histoembryol Cytogenet, Paris, France

来源：

HUMAN MUTATION | 2011年 / 32卷 / 01期

关键词：

mitochondria; mitochondrial DNA; MELAS; NARP; respiratory chain deficiency; embryo; preimplantation genetic diagnosis; PREIMPLANTATION GENETIC DIAGNOSIS; MITOCHONDRIAL-DNA HETEROPLASMY; PRENATAL-DIAGNOSIS; LACTIC-ACIDOSIS; GERMLINE BOTTLENECKS; DIABETES-MELLITUS; RAPID SEGREGATION; POINT MUTATION; MELAS; SELECTION;

D O I：

10.1002/humu.21417

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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. (C) 2010 Wiley-Liss, Inc.

引用

页码：116 / 125

页数：10

共 59 条

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