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

Nature Genetics volume 22, pages 182–187 (1999)Cite this article

Abstract

X-linked dominant disorders that are exclusively lethal prenatally in hemizygous males have been described in human and mouse1. 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 males2,3. 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 interval5. 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.

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Figure 1: Phenotype of Bpa mice.
Figure 2: Structure, deduced amino acid sequence and mutation analysis of Nsdhl.
Figure 3
Figure 4: Sterol analysis of cultured skin fibroblasts from an affected adult Bpa1H female and schematic representation of the site of the enzymatic block.

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Acknowledgements

We thank M. Platzer and A. Rosenthal for helpful discussions and for sharing human sequence data; M.B. Gilbert, D. Clarke, L.M. Mitchell, R.N.A. Straw and J.S. Greystrong for performing genomic sequencing of the mouse BAC and cosmid; J. Durbin and B. VanDyke for help with photography; and A. Payne for helpful discussions concerning 3β-HSDs. These studies were supported by NIH R01 NS34953 and Children's Hospital Research Foundation, The Ohio State University (G.E.H.) and R01 LM05110 from the National Library of Medicine (W.M.).

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Author notes

  1. Xiao Yu Liu and Andrew W. Dangel: These authors contributed equally to this work.

Authors and Affiliations

  1. Children's Hospital Research Foundation and Department of Pediatrics, The Ohio State University, Columbus, 43205, Ohio, USA

    Xiao Yu Liu, Andrew W. Dangel, Wei Zhao & Gail E. Herman

  2. The Kennedy Krieger Institute and Department of Pediatrics, John Hopkins University, Baltimore, 21205, Maryland, USA

    Richard I. Kelley

  3. MRC Mouse Genome Centre and Mammalian Genetics Unit , Harwell, OX11 ORD, UK

    Paul Denny, Bruce Cattanach, Jo Peters, Ann-Marie Mallon, Mark A. Strivens, Rachael Bate & Stephen D.M. Brown

  4. MRC Human Genome Mapping Project Resource Centre, Hinxton, Cambridge, UK

    Marc Botcherby & Michael Rhodes

  5. Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, 37831, Tennessee, USA

    Patricia R. Hunsicker

  6. Department of Computer Science, The Pennsylvania State University, University Park, 16802, Pennsylvania, USA

    Webb Miller

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Correspondence to Gail E. Herman.

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Liu, X., Dangel, A., Kelley, R. et al. The gene mutated in bare patches and striated mice encodes a novel 3β-hydroxysteroid dehydrogenase. Nat Genet 22, 182–187 (1999). https://doi.org/10.1038/9700

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