Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation (original) (raw)

Nature volume 392, pages 923–926 (1998)Cite this article

Abstract

Primary or nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in which affected patients do not have any distinctive clinical or biochemical features in common apart from cognitive impairment1. Although it is present in approximately 0.15–0.3% of males2, most of the genetic defects associated with MRX, which may involve more than ten different genes, remain unknown3. Here we report the characterization of a new gene on the long arm of the X-chromosome (position Xq12) and the identification in unrelated individuals of different mutations that are predicted to cause a loss of function. This gene is highly expressed in fetal brain and encodes a protein of relative molecular mass 91K, named oligophrenin-1, which contains a domain typical of a Rho-GTPase–activating protein (rhoGAP)4,5. By enhancing their GTPase activity, GAP proteins inactivate small Rho and Ras proteins, so inactivation of rhoGAP proteins might cause constitutive activation of their GTPase targets. Such activation is known to affect cell migration and outgrowth of axons and dendrites in vivo6,7,8,. Our results demonstrate an association between cognitive impairment and a defect in a signalling pathway that depends on a Ras-like GTPase.

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Acknowledgements

We thank the members of the families for their participation in this study; F. Francis, G. Gacon and O. Dorseuil for critically reading the manuscript; and T. Brüls for cosmid clones. This work was supported in part by grants from the AFM, AP-HP, and the Fondation Jérôme Lejeune. P.B is supported by a Ph.D. fellowship from Ministère de la Recherche.

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Authors and Affiliations

  1. INSERM U129-ICGM, Faculté de Médecine Cochin, 24 rue du Faubourg Saint-Jacques, 75014, Paris, France
    Pierre Billuart, Thierry Bienvenu, Vincent des Portes, Marie Claude Vinet, Ramzi Zemni, Alain Carrié, Fabien Fauchereau, Cherif Beldjord, Axel Kahn & Jamel Chelly
  2. Centre Hospitalier Universitaire de Tours, Service de Génétique, Hôpital Bretonneau, 2 boulevard Tonnelle, 37044, Tours Cedex, France
    Nathalie Ronce, Sylvain Briault & Claude Moraine
  3. Max-Plank-Institute for Molecular Genetics, Ihnestrasse 73, Berlin-Dahlem, Germany
    Hugues Roest Crollius
  4. Centre Hospitalier Universitaire de Nancy, Laboratoire de Génétique, Rue du Morvan, 54511, Vandoeuvre les Nancy Cedex, France
    Michele Cherry
  5. University Hospital Nijmegen, 417 Department of Human Genetics, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands
    Ben Hamel
  6. Center for Human Genetics, Clinical Genetics Univ, UZ Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium
    Jean-Pierre Fryns

Authors

  1. Pierre Billuart
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  2. Thierry Bienvenu
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  3. Nathalie Ronce
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  4. Vincent des Portes
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  5. Marie Claude Vinet
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  6. Ramzi Zemni
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  7. Hugues Roest Crollius
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  8. Alain Carrié
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  9. Fabien Fauchereau
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  10. Michele Cherry
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  11. Sylvain Briault
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  12. Ben Hamel
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  13. Jean-Pierre Fryns
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  14. Cherif Beldjord
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  15. Axel Kahn
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  16. Claude Moraine
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  17. Jamel Chelly
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Billuart, P., Bienvenu, T., Ronce, N. et al. Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation.Nature 392, 923–926 (1998). https://doi.org/10.1038/31940

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