A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation

X-linked forms of mental retardation (MR) affect approximately 1 in 600 mal es and are likely to be highly heterogeneous(1-3) They can be categorized i nto syndromic (MRXS) and nonspecific (MRX) forms. In MRX forms, affected pa tients 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 cases(4,5). Here we show that the gene TM4SF2 at Xp1 1.4 is inactivated by the X breakpoint of an X;2 balanced translocation in a patient with MR. Further investigation led to identification of TM4SF2 mu tations in 2 of 33 other MRX families. RNA in site hybridization showed tha t TM4SF2 is highly expressed in the central nervous system, including the c erebral cortex and hippocampus. TM4SF2 encodes a member of the tetraspanin family of proteins, which are known to contribute in molecular complexes in cluding beta-l integrins(6-8). We speculate that through this interaction, TM4SF2 might have a role in the control of neurite outgrowth.