X-linked forms of mental retardation (MR) affect approximately 1 in 600 males and are likely to be highly heterogeneous1,2,3. They can be categorized into syndromic (MRXS) and nonspecific (MRX) forms. In MRX forms, affected patients have no distinctive clinical or biochemical features. At least five MRX genes have been identified by positional cloning, but each accounts for only 0.5%–1.0% of MRX cases4,5. Here we show that the gene TM4SF2 at Xp11.4 is inactivated by the X breakpoint of an X;2 balanced translocation in a patient with MR. Further investigation led to identification of TM4SF2 mutations in 2 of 33 other MRX families. RNA in situ hybridization showed that TM4SF2 is highly expressed in the central nervous system, including the cerebral cortex and hippocampus. TM4SF2 encodes a member of the tetraspanin family of proteins, which are known to contribute in molecular complexes including β-1 integrins6,7,8. We speculate that through this interaction, TM4SF2 might have a role in the control of neurite outgrowth.
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We thank the patients and other family members for participation; members of the European XLMR consortium and T. Meitinger for contribution to this work and helpful discussions; the Resource Center of the German Human Genome Project at the Max-Planck-Insitute for Molecular Genetics for providing biological material; and members of Banque de cellules de Cassini for technical assistance. This work was supported in part by grants from the Human Frontier Scientific program, INSERM, including an APEX program 4X007E; La Fondation pour la Recherche Médicale; the Association Française contre les Myopathies; and The Fondation Jérôme Lejeune. R.Z. is a recipient of La Fondation pour la Recherche Médicale.
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