Abstract
Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Among the four loci causing AD-HSP identified so far, the SPG4 locus at chromosome 2p21–p22 has been shown to account for 40–50% of all AD-HSP families. Using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval, we identified a candidate gene encoding a new member of the AAA protein family, which we named spastin. Sequence analysis of this gene in seven SPG4-linked pedigrees revealed several DNA modifications, including missense, nonsense and splice-site mutations. Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues. The sequence homologies and putative subcellular localization of spastin suggest that this ATPase is involved in the assembly or function of nuclear protein complexes.
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References
Reid, E. Pure hereditary spastic paraplegia. J. Med. Genet. 34, 499–503 (1997).
Harding, A.E. Classification of the hereditary ataxias and paraplegias. Lancet 1, 1151–1155 (1983).
Werderlin, L. Hereditary ataxias. Occurence and clinical features. Acta Neurol. Scand. 73 (suppl. 106), 124 (1986).
Skre, H. Hereditary spastic paraplegia in western Norway. Clin. Genet. 6, 165–183 (1974).
Hazan, J. et al. Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to chromosome 14q. Nature Genet. 5, 163–167 (1993).
Hazan, J. et al. Linkage of a new locus for autosomal dominant familial spastic paraplegia to chromosome 2p. Hum. Mol. Genet. 3, 1569–1573 (1994).
Hentati, A. et al. Linkage of a locus for autosomal dominant familial spastic paraplegia to chromosome 2p markers. Hum. Mol. Genet. 3, 1867–1871 (1994).
Fink, J.K. et al. Autosomal dominant familial spastic paraplegia: tight linkage to chromosome 15q. Am. J. Hum. Genet. 56, 188–192 (1995).
Hedera, P. et al. Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q. Am. J. Hum. Genet. 64, 563–569 (1999).
The Hereditary Spastic Paraplegia Working Group. Hereditary spastic paraplegia: advances in genetic research. Neurology 46, 1507–1514 (1996).
Dürr, A. et al. Phenotype of autosomal dominant spastic paraplegia linked to chromosome 2. Brain 119, 1487–1496 (1996).
Scott, W.K. et al. Locus heterogeneity, anticipation, and reduction of the chromosome 2p minimal candidate region in autosomal dominant familial spastic paraplegia. Neurogenetics 1, 95–102 (1997).
Nielsen, J.E. et al. CAG repeat expansion in autosomal dominant pure spastic paraplegia linked to chromosome 2p21–24. Hum. Mol. Genet. 6, 1811–1816 (1997).
Hazan, J. et al. A fine integrated map of the SPG4 locus excludes an expanded CAG repeat in chromosome 2p-linked autosomal dominant spastic paraplegia. Genomics (in press).
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).
Saugier-Veber, P. et al. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nature Genet. 6, 257–262 (1994).
Confalonieri, F. & Duguet, M. A 200-amino acid ATPase module in search of a basic function. Bioessays 17, 639–650 (1995).
Patel, S. & Latterich, M. The AAA team: related ATPases with diverse functions. Trends Cell Biol. 8, 65–71 (1998).
Casari, G. et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983 (1998).
Heinzlef, O. et al. Mapping of a complicated familial spastic paraplegia to locus SPG4 on chromosome 2p. J. Med. Genet. 35, 89–93 (1998).
Ichida, K. et al. Cloning of the cDNA encoding human xanthine dehydrogenase (oxidase): structural analysis of the protein and chromosomal location of the gene. Gene 133, 279–284 (1993).
Andersson, S., Berman, D.M., Jenkins, E.P. & Russell, D.W. Deletion of steroid 5′-reductase 2 gene in male pseudohermaphroditism. Nature 354, 159–161 (1991).
Kanzaki, T. et al. TGF-β 1 binding protein: a component of the large latent complex of TGF-β 1 with multiple repeat sequences. Cell 61, 1051–1061 (1990).
Schnall, R. et al. Identification of a set of yeast genes coding for a novel family of putative ATPases with high similarity to constituents of the 26S protease complex. Yeast 10, 1141–1155 (1994).
Perier, F. et al. Identification of a novel mammalian member of the NSF/CDC48p/Pas1p/TBP-1 family through heterologous expression in yeast. FEBS Lett. 351, 286–290 (1994).
Solovyev, V.V., Salamov, A.A. & Lawrence, C.B. Predicting internal exons by oligonucleotide composition and discriminant analysis of spliceable open reading frames. Nucleic Acids Res. 22, 5156–5163 (1994).
Kulp, D., Haussler, D., Reese, M.G. & Eeckman, F.H. A generalized hidden Markov model for the recognition of human genes in DNA. in Proceedings of the Fourth International Conference on Intelligent Systems for Molecular Biology (ed. AAAI) 134–142 (MIT Press, St Louis, Missouri, 1996).
Xu, Y., Mural, R.J., Shah, M.B. & Uberbacher, E.C. Recognizing exons in genomic sequence using GRAIL II. in Genetic Engineering: Principles and Methods (ed. Setlow, J.) 241–253 (Plenum Press, New York, 1994).
Burge, C. & Karlin, S. Prediction of complete gene structure in human genomic DNA. J. Mol. Biol. 268, 78–94 (1997).
Kosak, M. Interpreting cDNA sequences: some insights from studies on translation. Mamm. Genome 7, 563–574 (1996).
Prestridge, D.S. Predicting Pol II promoter sequences using transcription factor binding sites. J. Mol. Biol. 249, 923–932 (1995).
Beyer, A. Sequence analysis of the AAA protein family. Protein Sci. 6, 2043–2058 (1997).
Walker, J.E., Saraste, M.J., Runswick, J.J. & Gay, N.J. Distantly related sequences in the α- and β-subunits of ATPase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide-binding fold. EMBO J. 1, 945–951 (1982).
Liberzon, A., Shpungin, S., Bangio, H., Yona, E. & Katcoff, D.J. Association of yeast SAP1, a novel member of the "AAA" ATPase family of proteins, with the chromatin protein SIN1. FEBS Lett. 388, 5–10 (1996).
Uberbacher, E.C. & Mural, R.J. Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. Proc. Natl Acad. Sci. USA 88, 11261–11265 (1991).
Swaffield, J.C. & Purugganan, M.D. The evolution of the conserved ATPase domain (CAD): reconstructing the history of an ancient protein module. J. Mol. Evol. 45, 549–563 (1997).
Neuwald, A.F., Aravind, L., Spouge, J.L. & Koonin, E.V. AAA+: a class of chaperone-like ATPases associated with the assembly, operation, and disassembly of protein complexes. Genome Res. 9, 27–43 (1999).
Hilt, W. & Wolf, D.H. Proteasomes of the yeast S. cerevisiae: genes, structure and functions. Mol. Biol. Reports 21, 3–10 (1995).
Ozelius, L.J. et al. The early onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nature Genet. 17, 40–48 (1997).
Wilkie, A.O.M. The molecular basis of genetic dominance. J. Med. Genet. 31, 89–98 (1994).
Hardy, J. & Gwinn-Hardy, K. Genetic classification of primary neurodegenerative disease. Science 282, 1075–1078 (1998).
Koutnikova, H. et al. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nature Genet. 16, 345–357 (1997).
Zhu, Z. et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nature Genet. 20, 337–343 (1998).
Saudou, F., Finkbeiner, S., Devys, D. & Greenberg, M.E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66 (1998).
Klement, I.A. et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95, 41–53 (1998).
Osoegawa, K. et al. An improved approach for construction of bacterial artificial chromosome libraries. Genomics 52, 1–8 (1998).
Ewing, B., Hillier, L., Wendl, M.C. & Green, P. Base-calling of automated sequencer traces using Phred. Genome Res. 8, 175–185 (1998).
Harris, N.L. Genotator: a workbench for sequence annotation. Genome Res. 7, 754–762 (1997).
Acknowledgements
We thank HSP family members and the Association Strümpell-Lorrain for participating in this study; C. Allaire for collecting family 4014; T. Maisonobe for performing the muscle biopsy; C. Caloustian, J.-P. Fiawoumo, F. Gary and D. Torchard for sequencing help; S. Cure for critical reading of the manuscript; and C. Fizames, S. Fauré, G. Gyapay, A. Lemainque, J.-L. Petit, M. Salanoubat, T. Bruls, M. Meugnier, W. Saurin, I. Richard and A. Bernot for discussions and support. The initial part of this work was funded by the Association Française contre les Myopathies.
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Hazan, J., Fonknechten, N., Mavel, D. et al. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet 23, 296–303 (1999). https://doi.org/10.1038/15472
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DOI: https://doi.org/10.1038/15472
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