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

Nat Genet. 2000 Oct;26(2):247-50. doi: 10.1038/80002.


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 retardation. So far, seven X-chromosomal genes mutated in nonspecific mental retardation (MRX) have been identified: FMR2, GDI1, RPS6KA3, IL1RAPL, TM4SF2, OPHN1 and PAK3 (refs 2-9). The products of the latter two have been implicated in regulation of neural plasticity by controlling the activity of small GTPases of the Rho family. Here we report the identification of a new MRX gene, ARHGEF6 (also known as alphaPIX 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 rearrangement. Mutation screening of 119 patients with nonspecific mental retardation revealed a mutation in the first intron of ARHGEF6 (IVS1-11T-->C) in all affected males in a large Dutch family. The mutation resulted in preferential 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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Cycle Proteins / genetics*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 21*
  • Female
  • Genetic Linkage
  • Genetic Markers
  • Guanine Nucleotide Exchange Factors / genetics*
  • Humans
  • Intellectual Disability / enzymology
  • Intellectual Disability / genetics*
  • Introns
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Rho Guanine Nucleotide Exchange Factors
  • Translocation, Genetic*
  • X Chromosome*
  • rho GTP-Binding Proteins / genetics*


  • ARHGEF6 protein, human
  • Cell Cycle Proteins
  • Genetic Markers
  • Guanine Nucleotide Exchange Factors
  • Rho Guanine Nucleotide Exchange Factors
  • rho GTP-Binding Proteins

Associated data

  • GENBANK/AF207831