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

The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

“…Similar phenotypic alterations, such as malformation of the nervous system, have also been observed in other mutant mice with a defect in cholesterol biosynthesis (Liu et al 1999, Tozawa et al 1999, Fitzky et al 2001. Interestingly, the mutant mice deficient in Ebp, Sc5d, Dhcr24 and Dhcr7 survive until birth (Derry et al 1999, Fitzky et al 2001, Krakowiak et al 2003, Wechsler et al 2003, Mirza et al 2006, while the HSD17B7KO and mice deficient in the steps prior to the HSD17B7 (Liu et al 1999, Tozawa et al 1999, Caldas et al 2005) present with embryonic lethal phenotypes.…”

Changes in gene expression associated with loss of function of the NSDHL sterol dehydrogenase in mouse embryonic fibroblasts

“…The most consistent defect observed in embryos that progress beyond E9.5 is a poorly developed placenta, specifically in the labyrinth, where embryonic blood vessels fail to invade the trophoblast layer and proliferate to provide an interface for gas and nutrient exchange with maternal blood sinuses (13). Total sterol and cholesterol levels are equivalent between mutant and wt embryos, suggesting that the lethality is not caused by simple cholesterol deficiency.…”

“…All of the seven known mutant murine Nsdhl alleles produce a characteristic striping of the coat in heterozygous females that follows the lines of X inactivation, and all of the mutations are lethal by embryonic day 13.5 (E13.5) in hemizygous males (9,12,13). The Bpa 1H allele, resulting from the nonsense mutation K103X, produces the most severe phenotype in surviving females, with asymmetric dwarfing and skeletal dysplasia, early postnatal patchy hyperkeratotic skin eruptions, and occasional microphthalmia and/or cataracts.…”

“…The majority of hemizygous Bpa 1H males die by E9.5. Evidence from sterol analyses of affected male embryos for two less severe Nsdhl alleles suggests that the male lethality is not attributable to simple cholesterol deficiency, because cholesterol and total sterol levels in affected male embryos are comparable to those of wild-type ( wt ) littermates, probably as a result of maternal transfer across the placenta (13).…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…The original Bpa 1H allele has the most severe phenotype and results from a nonsense mutation, K103×, which is predicted to be a null. All of the known Nsdhl alleles are prenatally lethal in affected male embryos ( 295 ). Male lethality for moderate ( Bpa 8H ) and mild ( Str 1H , Str 1Or ) alleles occurs at midgestation (E10.5-12.5) and is associated with a thin and poorly vascularized fetal placental labyrinth and yolk sac ( 295 ).…”