Letters to Nature
Nature 392, 923-926 (30 April 1998) | doi:10.1038/31940; Received 31 October 1997; Accepted 20 February 1998
Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation
Pierre Billuart1, Thierry Bienvenu1, Nathalie Ronce2, Vincent des Portes1, Marie Claude Vinet1, Ramzi Zemni1, Hugues Roest Crollius3, Alain Carrié1, Fabien Fauchereau1, Michele Cherry4, Sylvain Briault2, Ben Hamel5, Jean-Pierre Fryns6, Cherif Beldjord1, Axel Kahn1, Claude Moraine2 & Jamel Chelly1
- INSERM U129-ICGM, Faculté de Médecine Cochin, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France
- Centre Hospitalier Universitaire de Tours, Service de Génétique, Hôpital Bretonneau, 2 boulevard Tonnelle, 37044 Tours Cedex, France
- Max-Plank-Institute for Molecular Genetics, Ihnestrasse 73, Berlin-Dahlem, Germany
- Centre Hospitalier Universitaire de Nancy, Laboratoire de Génétique, Rue du Morvan, 54511 Vandoeuvre les Nancy Cedex, France
- University Hospital Nijmegen, 417 Department of Human Genetics, Geert Grooteplein 10, 6500 HB Nijmegen, The Netherlands
- Center for Human Genetics, Clinical Genetics Univ, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
Correspondence to: Correspondence and requests for materials should be addressed to J.C. (e-mail: Email: chelly@cochin.inserm.fr).The EMBL accession number for the oligophrenin-1 sequence reported here is AJ001189.
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 vivo 6, 7, 8,. Our results demonstrate an association between cognitive impairment and a defect in a signalling pathway that depends on a Ras-like GTPase.
