title: Maternally transmitted severe glucose 6-phosphate dehydrogenase deficiency is an embryonic lethal.
abstract: Mouse chimeras from embryonic stem cells in which the X-linked glucose 6-phosphate dehydrogenase (G6PD) gene had been targeted were crossed with normal females. First-generation (F(1)) G6PD(+/-) heterozygotes born from this cross were essentially normal; analysis of their tissues demonstrated strong selection for cells with the targeted G6PD allele on the inactive X chromosome. When these F(1) G6PD(+/-) females were bred to normal males, only normal G6PD mice were born, because: (i) hemizygous G6PD(-) male embryos died by E10.5 and their development was arrested from E7.5, the time of onset of blood circulation; (ii) heterozygous G6PD(+/-) females showed abnormalities from E8.5, and died by E11.5; and (iii) severe pathological changes were present in the placenta of both G6PD(-) and G6PD(+/-) embryos. Thus, G6PD is not indispensable for early embryo development; however, severe G6PD deficiency in the extraembryonic tissues (consequent on selective inactivation of the normal paternal G6PD allele) impairs the development of the placenta and causes death of the embryo. Most importantly, G6PD is indispensable for survival when the embryo is exposed to oxygen through its blood supply.
authors.affiliation: Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: Letizia
authors.initials: L
authors.lastname: Longo
authors.forename: Olga Camacho
authors.initials: OC
authors.lastname: Vanegas
authors.forename: Meghavi
authors.initials: M
authors.lastname: Patel
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rosti
authors.forename: Haiqing
authors.initials: H
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Waka
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Rosario
authors.initials: R
authors.lastname: Notaro
authors.forename: Katia
authors.initials: K
authors.lastname: Manova
authors.forename: Lucio
authors.initials: L
authors.lastname: Luzzatto
mesh_terms: D000483:Alleles; D000818:Animals; D003433:Crosses, Genetic; D004303:Dosage Compensation, Genetic; D004622:Embryo, Mammalian / Q000002:abnormalities; D005260:Female; D005313:Fetal Death / Q000201:enzymology / Q000235:genetics; D005804:Genes, Lethal; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000196:embryology / Q000235:genetics*; D006410:Hematopoiesis; D006579:Heterozygote; D008297:Male; D051379:Mice; D010641:Phenotype; D010920:Placenta / Q000098:blood supply / Q000378:metabolism; D010929:Placentation; D011247:Pregnancy; D013234:Stem Cells / Q000378:metabolism; D014960:X Chromosome
chemical_list: D005954:Glucosephosphate Dehydrogenase