Placental defects are associated with male lethality in bare patches and striated embryos deficient in the NAD(P)H Steroid Dehydrogenase-like (NSDHL) Enzyme

Hugo Caldas, David Cunningham, Xiaojian Wang, Fenglei Jiang, Leon Humphries, Richard I. Kelley, Gail E. Herman

Research output: Contribution to journalArticlepeer-review

Abstract

NSDHL is a 3β-hydroxysterol dehydrogenase that is involved in the removal of C-4 methyl groups in one of the later steps of cholesterol biosynthesis. Mutations in the Nsdhl gene are associated with the X-linked male lethal mouse mutations bare patches (Bpa) and striated (Str), as well as with most cases of human CHILD syndrome. To begin to examine the pathogenesis of these disorders, we have determined that affected male embryos for several Nsdhl alleles die in midgestation, between E10.5 and 13.5, while the majority of affected male embryos for the most severe allele, Nsdhl Bpa1H, die prior to E9.5. Although no consistent anomalies were identified in affected male embryos themselves, the labyrinth layer of the fetal placenta was always thinner, with fewer fetal vessels and decreased proliferation of labyrinth trophoblast cells. X-inactivation is non-random in females in most lineages of the rodent placenta with preferential inactivation of the paternal X chromosome. For primary defects involving these extraembryonic lineages, heterozygous females with a mutant maternal X chromosome would be expected to have an identical placental phenotype to that found in affected male embryos. We hypothesize that abnormalities in cells of the allantoic mesoderm that undergo random X-inactivation and form the endothelial lining of the fetal vessels of the labyrinth are associated with the male lethality, perhaps through disruption of an as yet unidentified signaling pathway.

Original languageEnglish (US)
Pages (from-to)48-60
Number of pages13
JournalMolecular genetics and metabolism
Volume84
Issue number1
DOIs
StatePublished - Jan 2005

Keywords

  • Bare patches
  • CHILD syndrome
  • Cholesterol biosynthesis
  • NSDHL
  • Placenta
  • X-inactivation

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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