The gene mutated in bare patches and striated mice encodes a novel 3β-hydroxysteroid dehydrogenase

Abstract

X-linked dominant disorders that are exclusively lethal prenatally in hemizygous males have been described in human and mouse. None of the genes responsible has been isolated in either species. The bare patches (Bpa) and striated (Str) mouse mutations were originally identified in female offspring of X-irradiated males. Subsequently, additional independent alleles were described. We have previously mapped these X-linked dominant, male-lethal mutations to an overlapping region of 600 kb that is homologous to human Xq28 (ref. 4) and identified several candidate genes in this interval. Here we report mutations in one of these genes, Nsdhl, encoding an NAD(P)H steroid dehydrogenase-like protein, in two independent Bpa and three independent Str alleles. Quantitative analysis of sterols from tissues of affected Bpa mice support a role for Nsdhl in cholesterol biosynthesis. Our results demonstrate that Bpa and Str are allelic mutations and identify the first mammalian locus associated with an X-linked dominant, male-lethal phenotype. They also expand the spectrum of phenotypes associated with abnormalities of cholesterol metabolism.

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

“…Furthermore, heart development was affected, and we observed pericardial effusion, reduced number of myocardial cells and thin pericardium . 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.…”

Molecular and Enzymatic Characterizations of Novel Bifunctional 3β-Hydroxysteroid Dehydrogenases/C-4 Decarboxylases from Arabidopsis thaliana

“…3). The protein sequences of At3␤HSD/D1 and At3␤HSD/D2 show 30% identity with the yeast ERG26 protein (13) and 37% identity with the NAD(P)H steroid dehydrogenase-like protein from animals (28). These clones show 22% identity with the human 3␤-hydroxysteroid dehydrogenase/isomerase (29 -30) and 26% identity with the cholesterol dehydrogenase from Nocardia (31), all enzymes catalyzing dehydrogenation of 3␤-hydroxysteroids.…”

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

“…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.…”

“…One of these mouse models is the X-linked, male-lethal bare patches ( Bpa ) mouse resulting from mutations in the NADPH steroid dehydrogenase-like ( Nsdhl ) gene (9). Nsdhl encodes a ubiquitously expressed 362 amino acid protein that functions as a 3 ␤ -hydroxysterol dehydrogenase and is involved in the removal of C-4 methyl groups at an intermediate step in the conversion of lanosterol to cholesterol.…”