Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

PAK3 mutation in nonsyndromic X-linked mental retardation

Nature Genetics volume 20, pages 25–30 (1998)Cite this article

Abstract

Nonsyndromic X-linked mental retardation (MRX) syndromes are clinically homogeneous but genetically heterogeneous disorders, whose genetic bases are largely unknown. Affected individuals in a multiplex pedigree with MRX (MRX30), previously mapped to Xq22, show a point mutation in the PAK3 (p21-activated kinase) gene, which encodes a serine-threonine kinase. PAK proteins are crucial effectors linking Rho GTPases to cytoskeletal reorganization and to nuclear signalling. The mutation produces premature termination, disrupting kinase function. MRI analysis showed no gross defects in brain development. Immunofluorescence analysis showed that PAK3 protein is highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus. Signal transduction through Rho GTPases and PAK3 may be critical for human cognitive function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genomic organization of human PAK3 and cDNA contig.
Figure 2: Pedigree of the MRX30 family and mutation analysis of PAK3 in MRX30.
Figure 3: The MRX30 mutation encodes a stable, truncated protein without kinase activity but with preserved Cdc42 binding.
Figure 4: Expression analysis of PAK3 mRNA and protein.
Figure 5: Immunohistochemical analysis of Pak3 protein expression in developing mouse and adult rat cortex.

Similar content being viewed by others

References

  1. Gleeson, J.G. et al. doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 92, 63–72 (1998).

    Article  CAS  Google Scholar 

  2. Antonarakis, S. & Van Aelst, L. Mind the GAP, Rho, Rab and GDI. Nature Genet. 19, 106– 108 (1998).

    Article  CAS  Google Scholar 

  3. Gedeon, A., Donnelly, A., Mulley, J., Kerr, B. & Turner, G. How many X-linked genes for nonspecific mental retardation (MRX) are there? Am. J. Med. Genet. 64, 158–162 (1996).

    Article  CAS  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  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Nobes, C. & Hall, A. Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81, 53–62 (1995).

    Article  CAS  Google Scholar 

  7. Kaufmann, N., Wills, Z.P. & Van Vactor, D. Drosophila Rac1 controls motor axon guidance. Development 125, 453–461 (1998).

    CAS  PubMed  Google Scholar 

  8. Luo, L., Liao, Y., Jan, L. & Jan, Y. Distinct morphogenetic roles of similar small GTPases: Drosophila Drac1 is involved in axonal outgrowth and myoblast fusion. Genes Dev. 8, 1787– 1802 (1994).

    Article  CAS  Google Scholar 

  9. Luo, L., Jan, L. & Jan, Y. Rho family small GTP-binding proteins in growth cone signalling. Curr. Opin. Neurobiol. 7, 81–86 (1997).

    Article  CAS  Google Scholar 

  10. Zipkin, I., Kindt, R. & Kenyon, C. Role of a new rho family member in cell migration and axon guidance in C. elegans. Cell 90, 883 –894 (1997).

    Article  CAS  Google Scholar 

  11. Threadgill, R., Bobb, K. & Ghosh, A. Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42. Neuron 19, 625–634 ( 1997).

    Article  CAS  Google Scholar 

  12. Luo, L. et al. Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines. Nature 379, 837–840 (1996).

    Article  CAS  Google Scholar 

  13. Allen, K., Gleeson, J., Shoup, S. & Walsh, C. A YAC contig in Xq22.3-q23, from DXS287 to DXS8088, spanning the brain-specific genes doublecortin and PAK3. Genomics, in press.

  14. Bagrodia, S., Taylor, S.J., Creasy, C.L., Chernoff, J. & Cerione, R.A. Identification of a mouse p21Cdc42/Rac activated kinase. J. Biol. Chem. 270, 22731 –22737 (1995).

    Article  CAS  Google Scholar 

  15. Manser, E. et al. Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family. J. Biol. Chem. 270, 25070–25078 (1995).

    Article  CAS  Google Scholar 

  16. Ogilvie, D.J. & James, L.A. End rescue from YACs using the vectorette. Methods Mol. Biol. 54, 131– 138 (1996).

    CAS  PubMed  Google Scholar 

  17. Donnelly, A.J., Partington, M.W., Ryan, A.K. & Mulley, J.C. Regional localisation of two non-specific X-linked mental retardation genes (MRX30 and MRX31). Am. J. Med. Genet. 64, 113–120 (1996).

    Article  CAS  Google Scholar 

  18. Bokoch, G.M. et al. Interaction of the Nck adapter protein with p21-activated kinase (PAK1). J. Biol. Chem. 271, 25746 –25749 (1996).

    Article  CAS  Google Scholar 

  19. Hanks, S.K. & Quinn, A.M. Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol. 200, 38–62 (1991).

    Article  CAS  Google Scholar 

  20. Sells, M.A. et al. Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr. Biol. 7, 202– 210 (1997).

    Article  CAS  Google Scholar 

  21. Gregg, R.G., Palmer, C., Kirkpatrick, S. & Simantel, A. Localization of a non-specific X-linked mental retardation gene, MRX23, to Xq23-q24. Hum. Mol. Genet. 5, 411– 414 (1996).

    Article  CAS  Google Scholar 

  22. Gu, X.X. et al. Localisation of a new gene for non-specific mental retardation to Xq22-q26 (MRX35). J. Med. Genet. 33, 52–55 (1996).

    Article  CAS  Google Scholar 

  23. Ryan, S.G. et al. Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing. Nature Genet. 17, 92–95 (1997).

    Article  CAS  Google Scholar 

  24. Illarioshkin, S.N. et al. X-linked nonprogressive congenital cerebellar hypoplasia: clinical description and mapping to chromosome Xq. Ann. Neurol. 40, 75–83 ( 1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Bagrodia, S., Derijard, B., Davis, R.J. & Cerione, R.A. Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation. J. Biol. Chem. 270, 27995–27998 (1995).

    Article  CAS  Google Scholar 

  27. Fischer, M., Kaech, S., Knutti, D. & Matus, A. Rapid actin-based plasticity in dendritic spines. Neuron 20, 847–854 (1998).

    Article  CAS  Google Scholar 

  28. Zhang, S. et al. Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1. J. Biol. Chem. 270, 23934–23936 (1995).

    Article  CAS  Google Scholar 

  29. Brown, J. et al. Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway. Curr. Biol. 6, 598– 605 (1996).

    Article  CAS  Google Scholar 

  30. Milner, B., Squire, L.R. & Kandel, E.R. Cognitive neuroscience and the study of memory. Neuron 20, 445–468 ( 1998).

    Article  CAS  Google Scholar 

  31. Osada, S., Izawa, M., Koyama, T., Hirai, S. & Ohno, S. A domain containing the Cdc42/Rac interactive binding (CRIB) region of p65PAK inhibits transcriptional activation and cell transformation mediated by the Ras-Rac pathway. FEBS Lett. 404, 227– 233 (1997).

    Article  CAS  Google Scholar 

  32. Daniels, R.H., Hall, P.S. & Bokoch, G.M. Membrane targeting of p21-activated kinase 1 (PAK1) induces neurite outgrowth from PC12 cells. EMBO J. 17, 754–764 (1998).

    Article  CAS  Google Scholar 

  33. Galisteo, M.L., Chernoff, J., Su, Y.C., Skolnik, E.Y. & Schlessinger, J. The adaptor protein Nck links receptor tyrosine kinases with the serine- threonine kinase Pak1. J. Biol. Chem. 271, 20997–21000 (1996).

    Article  CAS  Google Scholar 

  34. Lu, W., Katz, S., Gupta, R. & Mayer, B. Activation of Pak by membrane localization mediated by an SH3 domain from the adaptor protein Nck. Curr. Biol. 7, 85– 94 (1997).

    Article  CAS  Google Scholar 

  35. Manser, E. et al. Expression of constitutively active α-PAK reveals effects of the kinase on actin and focal complexes. Mol. Cell Biol. 17, 1129–1143 (1997).

    Article  CAS  Google Scholar 

  36. Murphy, T., Schnaar, R. & Coyle, J. Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake. FASEB J. 4, 1624–1633 (1990).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the patients who participated in this study. We thank the following individuals for providing DNA samples from pedigrees that ultimately did not show PAK3 mutations: S. Illarioshkin, S. Claes, S. Fritz, J.-J. Cassiman, S. Ryan and R. Gregg. We thank J. Gonzalez, E. Olsen and S. de la Calle for help with immunohistochemistry, Y. Feng and F. Watson for help with COS cell transfection and western blots, J. Fox for help with SSCP, T. Young-Poussaint for reviewing the MRI and S. Hong for technical assistance. K.M.A. was supported by an NRSA from the NIMH (MH10691) and by the Goldenson/Berenberg fellowship. J.G.G. was supported by an NSADA from the NINDS (5K12NS01701) and by an educational grant from Sigma Tau Pharmaceuticals. C.A.W. was supported by the Human Frontier Science Program and NIH RO1 NS 35129 from the NINDS. C.A.W. is a Scholar of the Rita Allen Foundation.

Author information

Authors and Affiliations

  1. Division of Neurogenetics, Beth Israel Deaconess Medical Center, and Programs in Neuroscience and Biological/Biomedical Sciences, Harvard Medical School, HIM 846, 77 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Kristina M. Allen, Joseph G. Gleeson & Christopher A. Walsh

  2. Department of Neurology, Children's Hospital Medical Center, Boston, Massachusetts, USA

    Joseph G. Gleeson

  3. Department of Molecular Medicine, Cornell University, Ithaca, New York, USA

    Shubha Bagrodia & Richard A. Cerione

  4. Hunter Genetics, University of Newcastle, New South Wales, Australia

    Michael W. Partington

  5. Queensland Clinical Genetics Service, Royal Children's Hospital, Herston, Brisbane, Q4029, Australia

    John C. MacMillan

  6. Department of Cytogenetics and Molecular Genetics, Centre for Medical Genetics, Women's and Children's Hospital, Adelaide, Australia

    John C. Mulley

Authors
  1. Kristina M. Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph G. Gleeson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shubha Bagrodia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael W. Partington
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John C. MacMillan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard A. Cerione
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John C. Mulley
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christopher A. Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher A. Walsh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Allen, K., Gleeson, J., Bagrodia, S. et al. PAK3 mutation in nonsyndromic X-linked mental retardation. Nat Genet 20, 25–30 (1998). https://doi.org/10.1038/1675

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/1675

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing