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Mutations in GDI1 are responsible for X-linked non-specific mental retardation

Nature Genetics volume 19, pages 134–139 (1998)Cite this article

A Correction to this article was published on 01 July 1998

Abstract

Rab GDP-dissociation inhibitors (GDI) are evolutionarily conserved proteins that play an essential role in the recycling of Rab GTPases required for vesicular transport through the secretory pathway. We have found mutations in the GDI1 gene (which encodes αGDI) in two families affected with X-linked non-specific mental retardation. One of the mutations caused a non-conservative substitution (L92P) which reduced binding and recycling of RAB3A, the second was a null mutation. Our results show that both functional and developmental alterations in the neuron may account for the severe impairment of learning abilities as a consequence of mutations in GDI1, emphasizing its critical role in development of human intellectual and learning abilities.

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Figure 1: Mutations in patients MRX41 and MRX48.
Figure 2: Western-blot analysis of αGDI in a normal individual and MRX patients.
Figure 3: Effect of the L92P mutation on RAB3A binding and recycling.
Figure 4: Gdi1 expression during mouse brain development.
Figure 5: Inhibition of axonal outgrowth of hippocampal neurons treated with Gdi1 antisense oligonucleotides.

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References

  1. Lubs, H.A. et al. XLMR genes: update 1996. Am. J. Med. Genet. 64, 147–157 (1996)

    Article  CAS  PubMed  Google Scholar 

  2. Verkerk, A.J. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991)

    Article  CAS  PubMed  Google Scholar 

  3. Turner, G., Webb, T., Wake, S. & Robinson, H. Prevalence of fragile X syndrome. Am. J. Med. Genet. 64, 196–197 (1996)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. Bione, S. et al. Transcriptional organization of a 450-Kb region of the human X chromosome, in Xq28. Proc. Natl. Acad. Sci. USA 90, 10977–10981 (1993)

    Article  CAS  PubMed  Google Scholar 

  7. Wu, S.K., Zeng, K., Wilson, I.A. & Balch, W.E. Structural insights into the function of Rab GDI superfamily. Trends Biochem. Sci. 21, 472–476 (1996)

    Article  CAS  PubMed  Google Scholar 

  8. Pfeffer, S.R., Dirac-Svejstrup, A.B. & Soldati, T. Rab GDP dissociation inhibitor: putting rab GTPases in the right place. J. Biol. Chem. 270, 17057–17059 (1995)

    Article  CAS  PubMed  Google Scholar 

  9. Sasaki, T. et al. Purification and characterization from bovine brain cytosol of a protein that inhibits the dissociation of GDP from and the subsequent binding of GTP to smg p25A, a ras p21-like GTP-binding protein. J. Biol. Chem. 265, 2333–2337 (1990)

    CAS  PubMed  Google Scholar 

  10. Fisher von Mollard, G., Stahl, B., Khokhlatchev, A., Suedhof, T.C. & Jahn, R. Rab3C is a synaptic vesicle protein that dissociates from synaptic vesicle after stimulation of exocytosis. J. Biol. Chem. 269, 10971–10974 (1994)

    Google Scholar 

  11. Fischer von Mollard, G., Stahl, B., Li, C., Suedhof, T.C. & Jahn, R. Rab proteins in regulated exocytosis. Trends Biochem. Sci. 19, 164–168 (1994)

    Article  CAS  PubMed  Google Scholar 

  12. Wang, Y., Okamoto, M., Schmitz, F., Hofmann, K. & Suedhof, T.C. Rim is a putative Rab3 effector in regulating synaptic-vesicle fusion. Nature 388, 593–598 (1997)

    Article  CAS  PubMed  Google Scholar 

  13. Geppert, M. et al. The role of Rab3A in neurotrasmitter release. Nature 369, 493–497 (1994)

    Article  CAS  PubMed  Google Scholar 

  14. Takai, Y., Sasaki, T., Shirataki, H. & Nakanishi, H. Rab3A small GTP-binding protein in Ca(2+)-dependent exocytosis. Genes Cells 1, 615–632 (1996)

    Article  CAS  PubMed  Google Scholar 

  15. Bean, A.J. & Scheller, R.H. Better late than never: a role for rabs late in exocytosis. Neuron 19, 751–754 (1997)

    Article  CAS  PubMed  Google Scholar 

  16. Suedhof, T.C. Function of Rab3 GDP-GTP exchange. Neuron 18, 519–522 (1997)

    Article  Google Scholar 

  17. Sedlacek, Z., Koneki, B., Korn, B., Klauck, S.M. & Poustka, A. Evolutionary conservation and genomic organization of XA P-4, an Xq28 gene coding for a human rab GDP-dissociation inhibitor (GDI) . Mamm. Genome 5, 633–639 (1994)

    Article  CAS  PubMed  Google Scholar 

  18. Chen, E.Y. et al. Long-range sequence analysis in Xq28: thirteen known and six candidate genes in 219.4 kb of high GC DNA between the RCP/GCP and G6PD loci . Hum. Mol. Genet. 5, 659–668 (1996)

    Article  CAS  PubMed  Google Scholar 

  19. des Portes, V. et al. A gene for dominant nonspecific X-linked mental retardation is located in Xq28. Am. J. Hum. Genet. 60, 903–909 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hamel, B.C.J. et al. A gene for non specific X-linked mental retardation (MRX41) is located in the distal segment of Xq28. Am. J. Med. Genet. 64, 131–133 (1996)

    Article  CAS  PubMed  Google Scholar 

  21. Ullrich, O. et al. Rab GDP dissociation inhibitor as a general regulator for the membrane association of rab proteins. J. Biol. Chem. 268, 18143 –18150 (1993)

    CAS  PubMed  Google Scholar 

  22. Claes, S. et al. X-linked severe mental retardation and a progressive neurological disorder in a Belgian family: clinical and genetic studies. Clin. Genet. 52, 155–161 ( 1997)

    Article  CAS  PubMed  Google Scholar 

  23. Schalk, I. et al. Structure and mutational analysis of Rab GDP-dissociation inhibitor. Nature 381, 42–48 ( 1996)

    Article  CAS  PubMed  Google Scholar 

  24. Casey, P.J. & Seabra, M.C. Protein prenyltransferases. J. Biol. Chem. 271, 5289–5292 (1996)

    Article  CAS  PubMed  Google Scholar 

  25. Garrett, M.G., Zahner, J.E., Cheney, C.M. & Novick, P.J. Gdi1p encodes a GDP dissociation inhibitor that plays an essential role in the yeast secretory pathway. EMBO J. 13, 1718–1728 (1994)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Novick, P. & Zerial, M. The diversity of Rab proteins in vesicle transport. Curr. Opin. Cell Biol. 9, 496 –504 (1997)

    Article  CAS  PubMed  Google Scholar 

  27. Bachner, D., Sedlacek, Z., Korn, B., Hameister, H. & Poustka, A. Expression patterns of two human genes coding for different rab GDP-dissociation inhibitors (GDIs), extremely conserved proteins involved in cellular transport. Hum. Mol. Genet. 4, 701–708 (1995)

    Article  CAS  PubMed  Google Scholar 

  28. Banker, G.A. & Cowan, W.M. Rat hippocampal neurons in dispersed cell culture. Brain Res. 126, 397–352 (1977)

    Article  CAS  PubMed  Google Scholar 

  29. Bartlett, W.P. & Banker, G.A. An electron microscopic study of the development of axons and dendrites by hippocampal neurons in culture. II. Synaptic relationships. J. Neurosci. 4, 1954–1965 (1984)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Geppert, M., Goda, Y., Stevens, C.F. & Suedhof, T.C. The small GTP-binding protein Rab3A regulates a late step in synaptic vescicles fusion. Nature 387, 810–814 ( 1997)

    Article  CAS  PubMed  Google Scholar 

  31. Castillo, P.E. et al. Rab3A is essential for mossy fibre long-term potentiation in the hippocampus . Nature 388, 590–593 (1997)

    Article  CAS  PubMed  Google Scholar 

  32. Cremers, F.P.M., van de Pol, T.J.R., van Kerkhoff, L.P.M., Wieringa, B. & Ropers, H.H. Cloning of a gene that is rearranged in patients with choroideremia. Nature 357, 674–677 (1990).

    Article  Google Scholar 

  33. Seabra M.C. Brown, M.S. & Goldstein, J.L. Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase . Science 259, 377–381 (1993)

    Article  CAS  PubMed  Google Scholar 

  34. Bione, S. et al. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nature Genet. 8, 323–327 (1994)

    Article  CAS  PubMed  Google Scholar 

  35. Spinardi, L., Mazars, R. & Theillet, C. Protocols for an improved detection of point mutations by SSCP. Nucleic Acids Res. 19, 4009 ( 1991)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gulisano, M., Broccoli, V., Pardini, C. & Boncinelli, E. Emx1 and Emx2 show different patterns of expression during proliferation and differentiation of the developing cerebral cortex in the mouse. Eur. J. Neurosci. 8, 1037–1050 (1996)

    Article  CAS  PubMed  Google Scholar 

  37. Burgaya, F., Menegon, A., Menegoz, M., Valtorta, F. & Girault, J.A. Focal adhesion kinase in rat central nervous system . Eur. J. Neurosci. 7, 1810–1821 (1995)

    Article  CAS  PubMed  Google Scholar 

  38. Dascher, C. & Balch, W.E. Dominant inhibitory mutants of ARF1 block endoplasmic reticulum to Golgi transport and trigger disassembly of the Golgi apparatus. J. Biol. Chem. 269, 1437–1448 (1994)

    CAS  PubMed  Google Scholar 

  39. Nuoffer, C., Peter, F. & Balch, W.E. Purification of His6-tagged Rab1 proteins using bacterial and insect cell expression systems. Methods Enzymol. 257, 3–8 (1995)

    Article  CAS  PubMed  Google Scholar 

  40. Fisher von Mollard, G., Suedhof, T.C. & Jahn R. Nature 349, 79–81 (1991).

    Article  Google Scholar 

  41. Dekker, L.V., De Graan, P.N.E., Pijnappel, P., Oestreicher, A.B. & Gispen, W.H. Noradrenaline release from streptolysin O-permeated rat cortical synaptosomes: effects of calcium, phorbol esters, protein kinase inhibitors, and antibodies to the neuron-specific protein kinase C substrate B-50 (GAP-43). J. Neurochem. 56, 1146–1153 (1991)

    Article  CAS  PubMed  Google Scholar 

  42. 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 

Download references

Acknowledgements

We thank P. Willems and A. Meindl for the DNA of patients MRX25 and MRX28, M. Zerial for the gift of the anti-αGDI antibodies, D. Dunlop for help with the computer program, E. Boncinelli for the hospitality to do in situ hybridizations; M. Gatti for skillful technical assistance, K. Zeng for preparation of the illustrations showing structural changes in αGDI and the Galliera Genetic Bank (program C23) for the patient samples. This work was funded by Telethon Italy (D.T. and F.V.) and by GM33301 and EY11606 (W.E.B.).

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Authors and Affiliations

  1. Institute of Genetics Biochemistry and Evolution, CNR, Pavia, Italy

    Patrizia D'Adamo, Filippo Tamanini & Daniela Toniolo

  2. DIBIT-HSR, Milano, Italy

    Andrea Menegon, Massimo Gulisano, Flavia Valtorta & Daniela Toniolo

  3. Laboratory of Human Genetics, Galliera Hospital, Genova, Italy

    Cristiana Lo Nigro & Marina Grasso

  4. Institute Cochin de Genetique Moleculaire, Paris, France

    Thierry Bienvenu & Jamel Chelly

  5. Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, North Adelaide, Australia

    Agi K. Gedeon

  6. Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands

    Ben Oostra

  7. Department of Molecular and Cell Biology, The Scripps Research Institute, La Jolla, California, USA

    Shih-Kwang Wu, Anurag Tandon & William E. Balch

  8. Department of Medical Pharmacology, University of Milano, Milano, Italy

    Flavia Valtorta

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Correspondence to Daniela Toniolo.

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D'Adamo, P., Menegon, A., Lo Nigro, C. et al. Mutations in GDI1 are responsible for X-linked non-specific mental retardation. Nat Genet 19, 134–139 (1998). https://doi.org/10.1038/487

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