Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation.
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. Although it is present in approximately 0.15-0.3% of males, most of the genetic defects associated with MRX, which may involve ... more than ten different genes, remain unknown. 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). 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. Our results demonstrate an association between cognitive impairment and a defect in a signalling pathway that depends on a Ras-like GTPase.
Mesh Terms:
Amino Acid Sequence, Animals, Central Nervous System, Chromosome Mapping, Cytoskeletal Proteins, Female, Frameshift Mutation, GTP Phosphohydrolases, GTP-Binding Proteins, GTPase-Activating Proteins, Gene Expression Regulation, Developmental, Guanosine Triphosphate, Humans, In Situ Hybridization, Fluorescence, Linkage (Genetics), Male, Mental Retardation, Molecular Sequence Data, Nuclear Proteins, Pedigree, Phosphoproteins, Polymerase Chain Reaction, Proteins, Recombinant Fusion Proteins, Sequence Deletion, Translocation, Genetic, X Chromosome, ras GTPase-Activating Proteins
Amino Acid Sequence, Animals, Central Nervous System, Chromosome Mapping, Cytoskeletal Proteins, Female, Frameshift Mutation, GTP Phosphohydrolases, GTP-Binding Proteins, GTPase-Activating Proteins, Gene Expression Regulation, Developmental, Guanosine Triphosphate, Humans, In Situ Hybridization, Fluorescence, Linkage (Genetics), Male, Mental Retardation, Molecular Sequence Data, Nuclear Proteins, Pedigree, Phosphoproteins, Polymerase Chain Reaction, Proteins, Recombinant Fusion Proteins, Sequence Deletion, Translocation, Genetic, X Chromosome, ras GTPase-Activating Proteins
Nature
Date: Apr. 30, 1998
PubMed ID: 9582072
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