Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation

X-linked forms of mental retardation (XLMR) include a variety of different disorders and may account for up to 25% of all inherited cases of mental re tardation(1). So far, seven X-chromosomal genes mutated in nonspecific ment al retardation (MRX) have been identified: FMR2, GDI1, RPS6KA3, IL1RAPL, TM 4SF2, OPHN1 and PAK3 (refs 2-9). The products of the latter two have been i mplicated in regulation of neural plasticity by controlling the activity of small GTPases of the Rho family. Here we report the identification of a ne w MRX gene. ARHGEF6 (also known as alpha PIX or Cool-2). encoding a protein with homology to guanine nucleotide exchange factors for Rho GTPases (Rho GEF). Molecular analysis of a reciprocal X/21 translocation in a male with mental retardation showed that this gene in Xq26 was disrupted by the rearr angement. Mutation screening of 119 patients with nonspecific mental retard ation revealed a mutation in the first intron of ARHGEF6 (IVS1-11T-->C) in all affected males in a large Dutch family(10). The mutation resulted in pr eferential skipping of exon 2. predicting a protein lacking 28 amino acids; . ARHGEF6 is the eighth MRX gene identified so far and the third such gene to encode a protein that interacts with Rho GTPases.