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Mutations in a Δ8-Δ7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata

Nature Genetics volume 22, pages 286–290 (1999)Cite this article

Abstract

Tattered (Td) is an X-linked, semi-dominant mouse mutation associated with prenatal male lethality1. Heterozygous females are small and at 4–5 days of age develop patches of hyperkeratotic skin where no hair grows, resulting in a striping of the coat in adults2. Craniofacial anomalies and twisted toes have also been observed in some affected females3,4. A potential second allele of Td has also been described5. The phenotype of Td is similar to that seen in heterozygous females with human X-linked dominant chondrodysplasia punctata (CDPX2, alternatively known as X-linked dominant Conradi-Hünermann-Happle syndrome) as well as another X-linked, semi-dominant mouse mutation, bare patches (Bpa). The Bpa gene has recently been identified6 and encodes a protein with homology to 3β-hydroxysteroid dehydrogenases that functions in one of the later steps of cholesterol biosynthesis. CDPX2 patients display skin defects including linear or whorled atrophic and pigmentary lesions, striated hyperkeratosis, coarse lusterless hair and alopecia, cataracts and skeletal abnormalities including short stature, rhizomelic shortening of the limbs, epiphyseal stippling and craniofacial defects (MIM 302960). We have now identified the defect in Td mice as a single amino acid substitution in the Δ8-Δ7 sterol isomerase emopamil binding protein (Ebp; encoded by Ebp in mouse) and identified alterations in human EBP in seven unrelated CDPX2 patients.

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Figure 1: Phenotypic analysis of Td.
Figure 2: Genetic mapping of Td.
Figure 3: EBP mutations in Td and CDPX2.
Figure 4: Sterol profiles in Td and sterol biosynthetic pathway.

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References

  1. Cattanach, B.M. A new X-linked mutation, Td. Mouse News Letter 66, 61–62 (1982).

    Google Scholar 

  2. Uwechue, I.C. et al. The mouse X-linked developmental mutant, tattered, lies between DXMit55 and Xkh and is associated with hyperkeratinization. Genomics 37, 238–241 ( 1996).

    Article  CAS  Google Scholar 

  3. Rasberry, C., Beechey, C. & Cattanach, B.M. Time of death of tattered males. Mouse Genome 93, 1028 (1995).

    Google Scholar 

  4. Uwechue, I.C. Analysis of X-linked mouse mutants. Thesis, Univ. Oxford ( 1997).

  5. Seo, K.W., Miyoshi, H., Kon, Y. & Watanabe, T. Chromosomal mapping and developmental study of Tattered-Hokkaido (Tdho). Mamm. Genome 8, 578–580 (1997).

    Article  CAS  Google Scholar 

  6. Liu, X.Y. et al. The gene mutated in bare patches and striated mice encodes a novel 3β-hydroxysteroid dehydrogenase. Nature Genet. 22, 182–187 (1999).

    Article  CAS  Google Scholar 

  7. Merrell, K., Gonzales, J.C., Wells, S., Calame, K. & Herman, G.E. Genetic analyses of tattered, an X-linked dominant, developmental mouse mutation. Mamm. Genome 6, 291–294 (1995).

    Article  CAS  Google Scholar 

  8. Silve, S. et al. Emopamil-binding protein, a mammalian protein that binds a series of structurally diverse neuroprotective agents, exhibits δ8-δ7 sterol isomerase activity in yeast. J. Biol. Chem. 271, 22434–22440 (1996).

    Article  CAS  Google Scholar 

  9. Kelley, R.I. et al. Abnormal sterol metabolism in patients with Conradi-Hünermann-Happle syndrome and sporadic lethal chondrodysplasia punctata. Am. J. Med. Genet. 83, 213–219 (1999).

    Article  CAS  Google Scholar 

  10. Hanner, M. et al. Phenylalkylamine Ca2+ antagonist binding protein. Molecular cloning, tissue distribution, and heterologous expression. J. Biol. Chem. 270, 7551–7557 (1995).

    Article  CAS  Google Scholar 

  11. Labit-Le Bouteiller, C. et al. Antiproliferative effects of SR31747A in animal cell lines are mediated by inhibition of cholesterol biosynthesis at the sterol isomerase step. Eur. J. Biochem. 256, 342– 349 (1998).

    Article  CAS  Google Scholar 

  12. Cho, S.Y., Kim, J.H. & Paik, Y.K. Cholesterol biosynthesis from lanosterol: differential inhibition of sterol Δ 8-isomerase and other lanosterol-converting enzymes by tamoxifen. Mol. Cells 8, 233– 239 (1998).

    CAS  PubMed  Google Scholar 

  13. Kelley, R.I. RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis. Am. J. Hum. Genet. 63, 322–326 (1998).

    Article  CAS  Google Scholar 

  14. Yoshizawa, T. et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nature Genet. 16, 391–396 (1997).

    Article  CAS  Google Scholar 

  15. Jones, G., Strugnell, S.A. & DeLuca, H.F. Current understanding of the molecular actions of vitamin D. Physiol. Rev. 78, 1193– 1231 (1998).

    Article  CAS  Google Scholar 

  16. Porter, J.A., Young, K.E. & Beachy, P.A. Cholesterol modification of hedgehog signaling proteins in animal development. Science 274, 255– 259 (1996).

    Article  CAS  Google Scholar 

  17. Farese, R.V. Jr & Herz, J. Cholesterol metabolism and embryogenesis. Trends Genet. 14, 115–120 (1998).

    Article  CAS  Google Scholar 

  18. Traupe, H. et al. Exclusion mapping of the X-linked dominant chondrodysplasia punctata/ichthyosis/cataract/short stature (Happle) syndrome: possible involvement of an unstable pre-mutation. Hum. Genet. 89, 659–665 (1992).

    Article  CAS  Google Scholar 

  19. Clayton, P.T., Kalter, D.C., Atherton, D.J., Besley, G.T. & Broadhead, D.M. Peroxisomal enzyme deficiency in X-linked dominant Conradi-Hunermann syndrome. J. Inherit. Metab. Dis. 12, 358–360 ( 1989).

    Article  Google Scholar 

  20. Holmes, R.D., Wilson, G.N. & Hajra, A.K. Peroxisomal enzyme deficiency in the Conradi-Hunerman form of chondrodysplasia punctata. N. Engl. J. Med. 316, 1608 (1987).

    CAS  PubMed  Google Scholar 

  21. Blair, H. & Boyd, Y. Tcfe3 maps close to Gata1 on the mouse X chromosome. Mouse Genome 92, 511–512 (1994).

    Google Scholar 

  22. Kelley, R.I. Diagnosis of Smith-Lemli-Opitz syndrome by gas chromatography/mass spectrometry of 7-dehydrocholesterol in plasma, amniotic fluid and cultured skin fibroblasts. Clin. Chim. Acta 236, 45– 58 (1995).

    Article  CAS  Google Scholar 

  23. Geraghty, M.T. et al. The isolation of cDNAs from OATL1 at Xp 11.2 using a 480-kb YAC. Genomics 16, 440–446 (1993).

    Article  CAS  Google Scholar 

  24. Derry, J.M., Kerns, J.A. & Francke, U. RBM3, a novel human gene in Xp11.23 with a putative RNA-binding domain. Hum. Mol. Genet. 4, 2307–2311 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. Pauli, G. Wilson, C. Kalter, J. Atherton, R. Stratton, W. Wilson and M. Levy for sharing clinical information and providing blood or tissue samples from human CDPX2 patients; N. Braverman and D. Valle for sharing data concerning their CDPX2 families before publication; G. Morriss-Kay and D. Papworth for discussions; and T. Hacker, L. Hobbs, W. Masson and D. Silber for technical assistance. This work was supported by NIH R01 NS34953 and the Children's Hospital Research Foundation, The Ohio State University (G.E.H.), an MRC HGMP studentship (E.G.) and direct support from the MRC (E.G., Y.B.).

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Authors and Affiliations

  1. Immunex Corporation, 51 University St , Seattle, 98101-2936, Washington, USA

    Jonathan M.J. Derry & Gary D. Means

  2. MRC Mammalian Genetics Unit, Harwell, OX11 0RD, UK

    Emmanuelle Gormally & Yvonne Boyd

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

    Wei Zhao & Gail E. Herman

  4. Abteilung Medizinische Genetik, Kinderpoliklinik der LMU, München, Germany

    Alfons Meindl

  5. Kennedy Krieger Institute and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Richard I. Kelley

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  1. Jonathan M.J. Derry
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Correspondence to Jonathan M.J. Derry.

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Derry, J., Gormally, E., Means, G. et al. Mutations in a Δ8-Δ7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata . Nat Genet 22, 286–290 (1999). https://doi.org/10.1038/10350

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