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

Abstract

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 retardation1. So far, seven X-chromosomal genes mutated in nonspecific mental retardation (MRX) have been identified: FMR2, GDI1, RPS6KA3, IL1RAPL, TM4SF2, OPHN1 and PAK3 (refs 29). 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 αPIX 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 family10. 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.

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Figure 1: Predicted genomic structure of ARHGEF6 and domain structure of the corresponding protein.
Figure 2: Mapping the translocation breakpoint by the analysis of cDNA and genomic DNA fragments from patient FCA.
Figure 3: Mutation analysis of ARHGEF6 in MRX46.
Figure 4: Analysis of the splice mutation and X-inactivation study in family MRX46.

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References

  1. Lubs, H. et al. XLMR genes: update 1998. Am. J. Med. Genet. 83, 237–247 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Gecz, J., Gedeon, A.K., Sutherland, G.R. & Mulley, J.C. Identification of the gene FMR2, associated with FRAXE mental retardation. Nature Genet. 13, 105–108 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Gu, Y., Shen, Y., Gibbs, R.A. & Nelson, D.L. Identification of FMR2, a novel gene associated with FRAXE CCG repeat and CpG island. Nature Genet. 13, 109–113 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. D'Adamo, P. et al. Mutations in GDI1 are responsible for X-linked non-specific mental retardation. Nature Genet. 19, 134–139 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Merienne, K. et al. A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation. Nature Genet. 22, 13–14 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Carrie, A. et al. A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nature Genet. 23, 25–31 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Zemni, R. et al. A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation. Nature Genet. 24, 167–170 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Billuart, P. et al. Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation. Nature 392, 923–926 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Allen, K.M. et al. PAK3 mutation in nonsyndromic X-linked mental retardation. Nature Genet. 20, 25–30 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Yntema, H.G. et al. Localisation of a gene for non-specific X linked mental retardation (MRX46) to Xq25–q26. J. Med. Genet. 35, 801–805 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. von Ballestrem, C.L. et al. Jumping translocation in a phenotypically normal female. Clin. Genet. 49, 156–159 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Nomura, N. et al. Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly sampled cDNA clones from human immature myeloid cell line KG-1. DNA Res. 1, 27–35 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Kozak, M. An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 15, 8125–8148 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Manser, E. et al. PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Mol. Cell 1, 183–192 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Boguski, M.S. & McCormick, F. Proteins regulating Ras and its relatives. Nature 366, 643–654 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Bourne, H.R., Sanders, D.A. & McCormick, F. The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348, 125–132 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Hart, M.J. et al. Cellular transformation and guanine nucleotide exchange activity are catalyzed by a common domain on the dbl oncogene product. J. Biol. Chem. 269, 62–65 (1994).

    CAS  PubMed  Google Scholar 

  18. Cerione, R.A. & Zheng, Y. The Dbl family of oncogenes. Curr. Opin. Cell Biol. 8, 216–222 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Katan, M. & Allen, V.L. Modular PH and C2 domains in membrane attachment and other functions. FEBS Lett. 452, 36–40 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Castresana, J. & Saraste, M. Does Vav bind to F-actin through a CH domain? FEBS Lett. 374, 149–151 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Shapiro, M.B. & Senapathy, P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 15, 7155–7174 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Allen, R.C., Zoghbi, H.Y., Moseley, A.B., Rosenblatt, H.M. & Belmont, J.W. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am. J. Hum. Genet. 51, 1229–1239 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Hall, A. Rho GTPases and the actin cytoskeleton. Science 279, 509–514 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Van Aelst, L. & D'Souza-Schorey, C. Rho GTPases and signaling networks. Genes Dev. 11, 2295–2322 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Gallo, G. & Letourneau, P.C. Axon guidance: GTPases help axons reach their targets. Curr. Biol. 8, R80–82 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Trivier, E. et al. Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 384, 567–570 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Bala, S., Sulekova, Z. & Ballhausen, W.G. Constitutive APC exon 14 skipping in early-onset familial adenomatous polyposis reveals a dramatic quantitative distortion of APC gene-specific isoforms. Hum. Mutat. 10, 201–206 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Bunge, S., Fuchs, S. & Gal, A. Simple and nonisotopic methods to detect unknown gene mutations in nucleic acids. in Methods in Molecular Genetics, Vol. 8 Human Molecular Genetics (eds Adolph, K.W. et al.) 26–39 (Academic, San Diego, 1996).

    Google Scholar 

  29. Weeks, D.E., Nygaard, T.G., Neystat, M., Harby, L.D. & Wilhelmsen, K.C. A high-resolution genetic linkage map of the pericentromeric region of the human X chromosome. Genomics 26, 39–46 (1995).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank N. Nomura for the KIAA0006 cDNA clone; B. van den Helm for technical assistance; C. Steglich and Z. Maroti for mutation screening; and I. Martinez Garay for hybridization of the multiple tissue expression array. This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (SFB444/Grundlagen neuraler Kommunikation und Signalverarbeitung) and the ZorgOnderzoek Netherland (ZON 28-2447-1).

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Kutsche, K., Yntema, H., Brandt, A. et al. Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nat Genet 26, 247–250 (2000). https://doi.org/10.1038/80002

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