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.

  • Letter
  • Published:

Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia

Abstract

The hereditary spastic paraplegias (HSPs; Strümpell-Lorrain syndrome, MIM number 18260) are a diverse class of disorders characterized by insidiously progressive lower-extremity spastic weakness (reviewed in refs. 13). Eight autosomal dominant HSP (ADHSP) loci have been identified, the most frequent of which is that linked to the SPG4 locus on chromosome 2p22 (found in 42%)1, followed by that linked to the SPG3A locus on chromosome 14q11–q21 (in 9%)1. Only SPG4 has been identified4 as a causative gene in ADHSP. Its protein (spastin) is predicted to participate in the assembly or function of nuclear protein complexes4. Here we report the identification of mutations in a newly identified GTPase gene, SPG3A, in ADHSP affected individuals.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: HSP kindreds linked to the SPG3A locus on chromosome 14q11–21.
Figure 2: Representative SPG3A sequence of normal and affected individuals of kindreds linked to the SPG3A locus.
Figure 3: SPG3A cDNA and atlastin protein sequences.
Figure 4: Sequence alignment of atlastin and homologs.
Figure 5: Predicted 3-D structures of atlastin and GBP1.
Figure 6: Multiple-tissue northern blot analysis of SPG3A expression.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Fink, J.K. et al. Hereditary spastic paraplegia: advances in genetic research. Neurology 46, 1507–1514 (1996).

    Article  CAS  Google Scholar 

  2. Fink, J.K. & Hedera, P. Hereditary spastic paraplegia: genetic heterogeneity and genotype-phenotype correlation. Semin. Neurol. 19, 301–310 (1999).

    Article  CAS  Google Scholar 

  3. Fink, J.K. Hereditary spastic paraplegia. In Emery,Rimoin's Principles and Practice of Medical Genetics Vol. 4 (eds Rimoin, D., Pyeritz, R., Connor, J. & Korf, B.) in press (Harcourt, London, 2001).

  4. Hazan, J. et al. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nature Genet. 23, 296–303 (1999).

    Article  CAS  Google Scholar 

  5. Rainier, S. et al. Hereditary spastic paraplegia linked to chromosome 14q11–q21: reduction of the SPG3 locus interval from 5.3 to 2.7 cM. J. Med. Genet. (in press) (2001).

  6. Casari, G. et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983 (1998).

    Article  CAS  Google Scholar 

  7. Jouet, M. et al. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nature Genet. 7, 402–407 (1994).

    Article  CAS  Google Scholar 

  8. Scheffzek, K., Reza, M. & Wittinghofer, A. GTPase-activating proteins: helping hands to complement an active site. Trends Biochem. Sci. 23, 257–262 (1998).

    Article  CAS  Google Scholar 

  9. Prakash, B., Renault, L., Praefcke, G.J.K., Herrmann, C. & Wittinghofer, A. Triphosphate structure of guanylate-binding protein 1 and implications for nucleotide binding and GTPase mechanism. EMBO J. 19, 4555–4564 (2000).

    Article  CAS  Google Scholar 

  10. Prakash, B., Praefcke, G.J.K., Renault, L., Wittinghofer, A. & Herrmann, C. Structure of human guanylate-binding protein 1 representing a unique class of GTP-binding proteins. Nature 403, 567–571 (2000).

    Article  CAS  Google Scholar 

  11. Sever, S., Muhlberg, A.B. & Schmid, S.L. Impairment of dynamin's GAP domain stimulates receptor-mediated endocytosis. Nature 398, 481–486 (1999).

    Article  CAS  Google Scholar 

  12. Schwemmle, M., Richter, M.F., Herrmann, C., Nassar, N. & Staeheli, P. Unexpected structural requirements for GTPase activity of the interferon-induced MxA protein. J. Biol. Chem. 270, 13518–13523 (1995).

    Article  CAS  Google Scholar 

  13. McNiven, M.A., Cao, H., Pitts, K.R. & Yoon, Y. The dynamin family of mechanoenzymes: pinching in new places (Review). Trends Biochem. Sci. 25, 115–120 (2000).

    Article  CAS  Google Scholar 

  14. Schmid, S.L., McNiven, M.A. & DeCamilli, P. Dynamin and its partners: a progress report. Curr. Opin. Cell Biol. 10, 504–512 (1998).

    Article  CAS  Google Scholar 

  15. Urrutia, R., Henley, J.R., Cook, T. & McNiven, M.A. The dynamins: redundant or distinct functions for an expanding family of related GTPases? Proc. Natl Acad. Sci. USA 94, 377–384 (1997).

    Article  CAS  Google Scholar 

  16. Noda, Y., Nakata, T. & Hirokawa, N. Localization of dynamin: widespread distribution in mature neurons and association with membranous organelles. Neuroscience 55, 113–127 (1993).

    Article  CAS  Google Scholar 

  17. Nicoziani, P. et al. Role for dynamin in late endosome dynamics and trafficking of the cation-independent mannose-6-phosphate receptor. Mol. Biol. Cell 11, 481–495 (2000).

    Article  CAS  Google Scholar 

  18. Jones, S.M., Howell, K.E., Henley, J.R., Cao, H. & McNiven, M.A. Role of dynamin in the formation of transport vesicles from the trans-Golgi network. Science 279, 573–577 (1998).

    Article  CAS  Google Scholar 

  19. Carroll, R.C. et al. Dynamin-dependent endocytosis of inotropic glutamate receptors. Proc. Natl Acad. Sci. USA 96, 14112–14117 (1999).

    Article  CAS  Google Scholar 

  20. Della Rocca, G.J. et al. Serotonin 5-HT1A receptor–mediated Erk activation requires calcium/calmodulin-dependent receptor endocytosis. J. Biol. Chem. 274, 4749–4753 (1999).

    Article  CAS  Google Scholar 

  21. Vogler, O. et al. Receptor subtype–specific regulation of muscarinic acetylcholine receptor sequestration by dynamin. Distinct sequestration of m2 receptors. J. Biol. Chem. 273, 12155–12160 (1998).

    Article  CAS  Google Scholar 

  22. Zhang, Y., Moheban, D.B., Conway, B.R., Bhattacharyya, A. & Segal, R.A. Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. J. Neurosci. 20, 5671–5678 (2000).

    Article  CAS  Google Scholar 

  23. Pitts, K.R., Yoon, Y., Krueger, E.W. & McNiven, M.A. The dynamin-like protein DLP1 is essential for normal distribution and morphology of the endoplasmic reticulum and mitochondria in mammalian cells. Mol. Biol. Cell 10, 4403–4417 (1999).

    Article  CAS  Google Scholar 

  24. Ochoa, G.C. et al. A functional link between dynamin and the actin cytoskeleton at podosomes. J. Cell. Biol. 150, 377–389 (2000).

    Article  CAS  Google Scholar 

  25. Hedera, P. et al. Prenatal diagnosis of hereditary spastic paraplegia. Prenatal Diagnosis 21, 202–206 (2001).

    Article  CAS  Google Scholar 

  26. Hedera, P., DiMauro, S., Bonilla, E., Wald, J.J. & Fink, J.K. Mitochondrial analysis in autosomal dominant hereditary spastic paraplegia. Neurology 55, 1591–1592 (2000).

    Article  CAS  Google Scholar 

  27. Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    Article  CAS  Google Scholar 

  28. Bairoch, A., Bucher, P. & Hofmann, K. The PROSITE database, its status in 1997. Nucleic Acids Res. 25, 217–221 (1997).

    Article  CAS  Google Scholar 

  29. Sali, A. & Blundell, T.L. Comparative protein modelling by satisfaction of spatial restraints. Biology 234, 779–815 (1993).

    CAS  Google Scholar 

  30. Laskowski, R.A., Rullmann, J.A., MacArthur, M.W., Kaptein, R. & Thornton, J.M. AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J. Biomol. NMR 8, 477–486 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the technical assistance of C. Deng, L. Nielsen, D. Tokarz, C. Delaney and D. Thomas, the expert secretarial assistance of L. Girbach and the participation of the patients with HSP and their families, without whom our investigations of HSP would not be possible. This research is supported by grants from the Veterans Affairs Merit Review and the National Institutes of Health (NINDS R01NS33645, R01NS36177 and R01NS38713) to J.K.F.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John K. Fink.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, X., Alvarado, D., Rainier, S. et al. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet 29, 326–331 (2001). https://doi.org/10.1038/ng758

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng758

This article is cited by

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