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A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans

Nature Genetics volume 22, pages 125–126 (1999)Cite this article

Steroidogenic factor-1 (SF-1, also known as Ad4BP) is an orphan nuclear receptor that regulates the transcription of an array of genes involved in reproduction, steroidogenesis and male sexual differentiation (for example, Amh, Ahch, Cyp11a, Star and those encoding steroid hydroxylases, gonadotropins and aromatase1). Disruption in mice of the gene encoding Sf-1, Ftzf1, causes failure of adrenal and gonadal development, XY sex reversal, persistence of Müllerian structures in males and abnormalities of the hypothalamus and pituitary gonadotropes1,2.

Direct DNA sequencing of FTZF1 (ref. 3) revealed a heterozygous 2-bp G35E (GGC→GAA) mutation in exon 3, which encodes part of the DNA-binding domain of SF-1 (Fig. 1b). The mutated glycine is the last amino acid in the proximal box (P-box) of the first zinc finger of SF-1 (Fig. 1c). This region is critical for the recognition of DNA binding sites4 and confers specificity to nuclear receptors in the regulation of target genes. Paternity was confirmed using multiple microsatellite markers (data not shown). The mutation creates a novel EcoRI site (GAATTC) that is not present in the parents of the patient (who have normal phenotype and sequence) or in 100 controls (200 alleles; Fig. 1d). Although we cannot exclude the possibility of an additional mutation elsewhere in the FTZF1 locus, direct sequence analysis of the remainder of the coding region, splice sites and promoter region (-873 to +143) did not reveal additional mutations. The coding sequences of other candidate genes, including SRY, STAR and AHC (formerly DAX1), are normal.

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Figure 1: Mutation in the SF-1 DNA-binding domain.
Figure 2: Functional analyses of mutant SF-1.

References

  1. Parker, K.L. & Schimmer, B.P. Endocr. Rev. 18, 361–377 (1997).

    Article  CAS  Google Scholar 

  2. Luo, X., Ikeda, Y. & Parker, K.L. Cell 77, 481–490 (1994).

    Article  CAS  Google Scholar 

  3. Wong, M., Ramayya, M.S., Chrousos, G.P., Driggers, P.H. & Parker, K.L. J. Mol. Endocrinol. 17, 139–147 (1996).

    Article  CAS  Google Scholar 

  4. Mader, S., Kumar, V., de Verneuil, H. & Chambon, P. Nature 338, 271–274 (1989).

    Article  CAS  Google Scholar 

  5. Lala, D.S., Rice, D.A. & Parker, K.L. Mol. Endocrinol. 6, 1249–1258 (1992).

    CAS  PubMed  Google Scholar 

  6. Giuili, G., Shen, W.H. & Ingraham, H.A. Development 124, 1799–1807 (1997).

    CAS  PubMed  Google Scholar 

  7. Bardoni, B. et al. Nature Genet. 7, 497–501 (1994).

    Article  CAS  Google Scholar 

  8. Foster, J.W. et al. Nature 372, 525–530 (1994).

    Article  CAS  Google Scholar 

  9. Pelletier, J. et al. Cell 67, 437–447 (1991).

    Article  CAS  Google Scholar 

  10. Barbaux, S. et al. Nature Genet. 17, 467–470 (1997).

    Article  CAS  Google Scholar 

  11. Swain, A., Narvaez, V., Burgoyne, P., Camerino, G. & Lovell-Badge, R. Nature 391, 761–767 (1998).

    Article  CAS  Google Scholar 

  12. Kreidberg, J.A. et al. Cell 74, 679–691 (1993).

    Article  CAS  Google Scholar 

  13. Nachtigal, M.W. et al. Cell 93, 445–454 (1998).

    Article  CAS  Google Scholar 

  14. Ito, M., Yu, R.N., Jameson, J.L. & Ito, M. J. Biol. Chem. 274, 9029–9037 (1999).

    Article  CAS  Google Scholar 

  15. Clemens, J.W., Lala, D.S., Parker, K.L. & Richards, J.S. Endocrinology 134, 1499–1508 (1994).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank G. Chrousos, M. Ramayya, K. Morohashi, C.G.D. Brook, E.J. Lee, R. Yu, L. Sabacan and T. Kotlar. J.C.A. acknowledges funding from the Special Trustees of the Middlesex Hospital and Endocrine Fellows Foundation. This work was performed as part of the National Cooperative Program for Infertility Research (NIH grant U54-HD-29164) and PO1 HD21921.

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  1. Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, 60611, Illinois, USA

    John C. Achermann, Masafumi Ito, Mika Ito & J. Larry Jameson

  2. London Centre for Paediatric Endocrinology, University College London, Cobbold Laboratories, Mortimer Street, London, W1N 8AA, UK

    Peter C. Hindmarsh

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Correspondence to J. Larry Jameson.

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Achermann, J., Ito, M., Ito, M. et al. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 22, 125–126 (1999). https://doi.org/10.1038/9629

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