Human Molecular Genetics Advance Access first published online on October 30, 2009
This version [Corrected Proof] published online on November 11, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp502
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Significant contributions of the extraembryonic membranes and maternal genotype to the placental pathology in heterozygous Nsdhl deficient female embryos
The Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
* To whom correspondence should be addressed at: Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, 700 Children's Dr. Rm W403, Columbus, OH 43205, USA. Tel: +1 6147222849; Fax: +1 6147222817; Email: gail.herman{at}nationwidechildrens.org
Received August 26, 2009; Revised October 5, 2009; Accepted October 28, 2009
Mutations in the gene encoding the cholesterol biosynthetic enzyme NSDHL are associated with the X-linked male-lethal bare patches (Bpa) mouse. Mutant male embryos for several Nsdhl alleles die in midgestation with placental insufficiency. We examined here a possible role of the maternal genotype in such placental pathology. Pre-pregnancy plasma cholesterol levels were similar between wild-type (WT) and Bpa1H/+ dams fed a standard, cholesterol-free diet. However, there was a marked decrease in cholesterol levels between embryonic day (E)8.5 and E10.5 for both genotypes. Further, there was a significant lag between E11.5 and E13.5 (P = 0.0011) in the recovery of levels in Bpa1H/+ dams to their pre-pregnancy values. To investigate possible effects of the maternal genotype on fetal placentation, we generated transgenic mice that expressed human NSDHL and rescued the male lethality of the Bpa1H null allele. We then compared placenta area at E10.5 in WT and Bpa1H/+ female embryos where the mutant X chromosome was transmitted from a heterozygous mother or a rescued mutant father. In mutant conceptuses, placental areas were 
50% less than WT. Surprisingly, expression of Nsdhl in trophoblast lineages of the placenta and yolk sac endoderm, which occurs only from the maternally inherited allele in a female embryo, had the largest effect on placental area (–0.681 mm2; P < 0.0001). The maternal genotype had a smaller effect, independent of the fetal genotype (–0.283 mm2; P = 0.024). These data demonstrate significant effects of the mother and fetal membranes on pregnancy outcome, with possible implications for cholesterol homeostasis during human pregnancy.