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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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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DOI: https://doi.org/10.1038/31940
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