Journal Article

Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation

Zemni, Ramzi, Cherry, Michele, Crollius, Hugues Roest, Fryns, Jean-Pierre, des Portes, Vincent, Hamel, Ben, Billuart, Pierre, Carrié, Alain, Vinet, Marie Claude, Chelly, Jamel, Fauchereau, Fabien, Beldjord, Cherif, Moraine, Claude, Ronce, Nathalie, Bienvenu, Thierry, Briault, Sylvain, Kahn, Axel

1998

Overview

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 impairment 1 . Although it is present in approximately 0.15–0.3% of males 2 , most of the genetic defects associated with MRX, which may involve more than ten different genes, remain unknown 3 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Amino Acid Sequence / Animals / Biochemistry, Molecular Biology / Biological and medical sciences / Birth defects / Central Nervous System - embryology / Central Nervous System - metabolism / Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...) / Chromosome Mapping / Cognition & reasoning / Cognitive ability / Cytoskeletal Proteins / Female / Frameshift Mutation / Gene Expression Regulation, Developmental / Genetic Linkage / Genetics / GTP Phosphohydrolases - metabolism / GTP-Binding Proteins - chemistry / GTP-Binding Proteins - genetics / GTP-Binding Proteins - metabolism / GTPase-Activating Proteins / Guanosine Triphosphate - metabolism / Humanities and Social Sciences / Humans / In Situ Hybridization, Fluorescence / Inactivation / Intellectual disabilities / Intellectual Disability - genetics / letter / Life Sciences / Male / Medical genetics / Medical sciences / Molecular Sequence Data / multidisciplinary / Nuclear Proteins - chemistry / Nuclear Proteins - genetics / Pedigree / Phosphoproteins - chemistry / Phosphoproteins - genetics / Polymerase Chain Reaction / Proteins / Proteins - metabolism / ras GTPase-Activating Proteins / Recombinant Fusion Proteins - metabolism / Science / Science (multidisciplinary) / Sequence Deletion / Translocation, Genetic / X Chromosome - genetics