Human Genetics

, Volume 90, Issue 4, pp 350–355 | Cite as

A familial mutation in the testis-determining gene SRY shared by both sexes

  • Ralf J. Jäger
  • Vincent R. Harley
  • Rudolf A. Pfeiffer
  • Peter N. Goodfellow
  • Gerd Scherer
Original Investigations

Abstract

A familial mutation in SRY, the gene coding for the testis-determining factor TDF, was identified in an XY female with gonadal dysgenesis, her father, her two brothers and her uncle. The mutation consists of a T to C transition in the region of the SRY gene coding for a protein motif known as the high mobility group (HMG) box, a protein domain known to confer DNA-binding specificity on the SRY protein. This point mutation results in the substitution, at amino acid position 109, of a serine residue for phenylalanine, a conserved aromatic residue in almost all HMG box motifs known. This F109S mutation was not found in 176 male controls. When recombinant wildtype SRY and SRYF109S mutant protein were tested in vitro for binding to the target site AAC AAAG, no differences in DNA-binding activity were observed. These results imply that the F109S mutation either is a rare neutral sequence variant, or produces an SRY protein with slightly altered in vivo activity, the resulting sex phenotype depending on the genetic back-ground or environmental factors.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Berta P, Hawkins JR, Sinclair HA, Taylor A, Griffiths BL, Goodfellow PN, Fellous M (1990) Genetic evidence equating SRY and the tesis-determining factor. Nature 348:448–450Google Scholar
  2. Casanova J-L, Pannetier C, Jaulin C, Kourilsky P (1990) Optimal conditions for directly sequencing double-stranded PCR products with Sequenase. Nucleic Acids Res 18:4028Google Scholar
  3. Diffley JFX, Stillman B (1991) A close relative of the nuclear, chromosomal high-mobility group protein HMG1 in yeast mitochondria. Proc Natl Acad Sci USA 88:7864–7868Google Scholar
  4. Eicher EM, Washburn LL (1986) Genetic control of primary sex determination in mice. Annu Rev Genet 20:327–360Google Scholar
  5. Gamier J, Osguthorpe DJ, Robson B (1978) Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol 120:97–120Google Scholar
  6. Giese K, Amsterdam A, Grosschedl R (1991) DNA-binding properties of the HMG domain of the lymphoid-specific transcriptional regulator LEF-1. Genes Dev 5:2567–2578PubMedGoogle Scholar
  7. Giese K, Cox J, Grosschedl R (1992) The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Cell 69:185–195Google Scholar
  8. Gubbay J, Collignon J, Koopman P, Capel B, Economou A, Münsterberg A, Vivian N, Goodfellow PN, Lovell-Badge R (1990) A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 346:245–250Google Scholar
  9. Haggren W, Kolodubretz D (1988) The Saccharomyces cerevisiae ACP2 gene encodes an essential HMG-1 like protein. Mol Cell Biol 8:1282–1289Google Scholar
  10. Harley VR, Jackson DI, Hextall PJ, Hawkins JR, Berkovitz GD, Sockanathan S, Lovell-Badge R, Goodfellow PN (1992) DNA binding activity of recombinant SRY from normal males and XY females. Science 255:453–456Google Scholar
  11. Harlow E, Lane D (1988) Antibodies: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NYGoogle Scholar
  12. Hawkins JR, Taylor A, Berta P, Levilliers J, Auwera B van der, Goodfellow PN (1992) Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum Genet 88:471–474Google Scholar
  13. Jäger RJ, Ebensperger C, Fraccaro M, Scherer G (1990a) A ZFY-negative 46,XX true hermaphrodite is positive for the Y pseudoautosomal boundary. Hum Genet 85:666–668Google Scholar
  14. Jäger RJ, Anvret M, Hall K, Scherer G (1990b) A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature 348:452–454Google Scholar
  15. Jäger RJ, Pfeiffer RA, Scherer G (1991) A familial amino acid substitution in SRY can lead to conditional XY sex inversion. Am J Hum Genet 49:s219Google Scholar
  16. Jantzen H-M, Admon A, Bell SP, Tjian R (1990) Nucleolar transcription factor hUBF contains a DNA-binding motif with homology to HMG proteins. Nature 344:830–836Google Scholar
  17. Koopman P, Münsterberg A, Capel B, Vivian N, Lovell-Badge R (1990) Expression of a candidate sex-determining gene during mouse testis differentiation. Nature 348:450–452Google Scholar
  18. Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R (1991) Male development of chromosomally female mice transgenic for Sry. Nature 351:117–121Google Scholar
  19. McElreavey KD, Vilain E, Boucekinne C, Vidaud M, Jaubert F, Richaud F, Fellous M (1992) XY sex reversal associated with a nonsense mutation in SRY. Genomics 12:838–840Google Scholar
  20. Nasrin N, Buggs C, Kong XF, Carnazza J, Goebl M, Alexander-Bridges M (1991) DNA-binding properties of the product of the testis-determining gene and a related protein. Nature 354:317–320Google Scholar
  21. Ner SS (1992) HMGs everywhere. Curr Biol 2:208–210Google Scholar
  22. Palmer MS, Sinclair AH, Berta P, Ellis NA, Goodfellow PN, Abbas NE, Fellous M (1989) Genetic evidence that ZFY is not the tesis-determining factor. Nature 342:937–939Google Scholar
  23. Pentecost BT, Wright JM, Dixon GH (1985) Isolation and sequence of cDNA clones for a member of the family of high mobility group proteins (HMG-T) in trout and analysis of HMG-T-mRNAs in trout tissues. Nucleic Acids Res 13:4871–4888Google Scholar
  24. Pivnick E, Wachtel S, Woods D, Simpson JL, Bishop C (1992) Mutations in the conserved domain of SRY are uncommon in XY gonadal dysgenesis. Hum Genet 90:308–310Google Scholar
  25. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory, Cold Spring Harbor, NYGoogle Scholar
  26. Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467PubMedGoogle Scholar
  27. Schauder B, Blöcker H, Frank R, McCarthy JEG (1987) Inducible expression vectors incorporating the Escherichia coli atpE translational initiation region. Gene 52:279–283Google Scholar
  28. Shirakata M, Hüppi K, Usuda S, Okazaki K, Yoshida K, Sakano H (1991) HMG1-related DNA-binding protein isolated with V-(D)-J recombinational signal probes. Mol Cell Biol 11:4528–4536Google Scholar
  29. Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf A-M, Lovell-Badge R, Good-fellow PN (1990) A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346:240–244Google Scholar
  30. Vilain E, McElreavy K, Jaubert F, Raymond J-P, Richaud F, Fellous M (1992) Familial case with sequence variant in the testisdetermining region associated with two sex phenotypes. Am J Hum Genet 50:1008–1011Google Scholar
  31. Wetering M van de, Clevers H (1992) Sequence-specific interaction of the HMG box proteins TCF-1 and SRY occurs within the minor groove of a Watson-Crick double helix. EMBO J 11:3039–3044Google Scholar
  32. Wetering M van de, Oosterwegel M, Dooijes D, Clevers H (1991) Identification and cloning of TCF-1, a T lymphocyte-specific transcription factor containing a sequence-specific HMG box. EMBO J 10:123–132PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Ralf J. Jäger
    • 1
  • Vincent R. Harley
    • 2
  • Rudolf A. Pfeiffer
    • 3
  • Peter N. Goodfellow
    • 2
  • Gerd Scherer
    • 1
  1. 1.Institut für Humangenetik und Anthropologie der UniversitätFreiburg i. Br.Germany
  2. 2.Human Molecular Genetics Laboratory. Imperial Cancer Research FundLondonUK
  3. 3.Institut für HumangenetikErlangenGermany

Personalised recommendations