Nature 348, 452 - 454 (29 November 1990); doi:10.1038/348452a0

A human XY female with a frame shift mutation in the candidate testis-determining gene SRY

Ralf J. Jäger^*, Maria Anvret^†, Kerstin Hall^‡ & Gerd Scherer^*§

^*Institute of Human Genetics, University of Freiburg, Breisacherstrasse 33, W-7800 Freiburg i.Br, Germany
^†Department of Clinical Genetics and ^‡ Department of Endocrinology, Karolinska Hospital, PO Box 60500, S-10401 Stockholm, Sweden
^§To whom correspondence should be addressed.

THE primary decision about male or female sexual development of the human embryo depends on the presence of the Y chromosome^1'2, more specifically on a gene on the Y chromosome encoding a testis-determining factor, TDF. The human sex-determining region has been delimited to a 35-kilobase interval near the Y pseudoautosomal boundary³. In this region there is a candidate gene for TDF, termed SRY, which is conserved and specific to the Y chromosome in all mammals tested3. The corresponding gene from the mouse Y chromosome is deleted in a line of XY female mutant mice, and is expressed at the expected stage during male gonadal development⁴. We have now identified a mutation in SRY in one out of 12 sex-inversed XY females with gonadal dysgenesis who do not lack large segments of the short arm of the Y chromosome^5-8. The four-nucleotide deletion occurs in a sequence of SRY encoding a conserved DNA-binding motif and results in a frame shift presumably leading to a non-functional protein. The mutation occurred de novo, because the father of the sporadic XY female that bears it has the normal sequence at the corresponding position. These results provide strong evidence for SRY being TDF.

References

1.	Ford, C. E. Miller, O. J., Polani, P. E., de Almeida, J. C. & Briggs, J. H. Lancet i, 711−713 (1959). | Article |
2.	Jacobs, P. A. & Strong, J. A. Nature 183, 302−303 (1959). | PubMed | ISI | ChemPort |
3.	Sinclair, A. H. et al. Nature 346, 240−244 (1990). | Article | PubMed | ISI | ChemPort |
4.	Gubbay, J. et al. Nature 346, 245−250 (1990). | Article | PubMed | ISI | ChemPort |
5.	Disteche, C. M. et al. Proc. natn. Acad. Sci. U.S.A. 83, 7841−7844 (1986). | ChemPort |
6.	Müller, U., Lalande, M., Donlon, T. Latt, S. A. Nucleic Acids Res. 14, 1325−1340 (1986). | PubMed |
7.	Affara, N. A. et al. Nucleic Acids Res. 15, 7325−7342 (1987). | PubMed | ChemPort |
8.	Levilliers, J., Quack, B., Weissenbach, J. & Petit, C. Proc. natn. Acad. Sci. U.S.A. 86, 2296−2300 (1989). | ChemPort |
9.	Page, D. C. et al. Cell 51, 1091−1104 (1987). | Article | PubMed | ISI | ChemPort |
10.	Simpson, J. L., Blagowidow, N. & Martin, A. O. Hum. Genet. 58, 91−97 (1981). | PubMed | ISI | ChemPort |
11.	Jantzen, H.-M., Admon, Admon, A., Bell, S. P. & Tjian, R. Nature 344, 830−836 (1990). | Article | PubMed | ISI | ChemPort |
12.	Farabough, P. J., Schmeissner, U., Hofer, M. & Miller, J. H. J. molec. Biol. 126, 847−857 (1978). | PubMed | ISI | ChemPort |
13.	Weber, J. L. & May, P. E. Am. J. hum. Genet. 44, 388−396 (1989). | PubMed | ISI | ChemPort |
14.	Schäfer, R., Zischler, H., Birsner, U., Becker, A. & Epplen, J. T. Electrophoresis 9, 369−374 (1988). | PubMed | ISI |
15.	Casanova, J.-L., Pannetier, C., Jaulin, C., Jaulin, C. & Kourilsky, P. Nucleic Acids Res. 18, 4028 (1990). | PubMed | ISI | ChemPort |