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Gene Review

SPAST  -  spastin

Homo sapiens

Synonyms: ADPSP, FSP2, KIAA1083, SPG4, Spastic paraplegia 4 protein, ...
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Disease relevance of SPAST


Psychiatry related information on SPAST

  • Here we report linkage to the SPG4 locus in a three generation family with AD-FSP complicated by dementia and epilepsy [6].

High impact information on SPAST

  • Comparative sequence analysis indicates that spartin shares similarity with molecules involved in endosomal trafficking and with spastin, a molecule implicated in microtubule interaction that is commonly mutated in HSP [7].
  • 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 approximately 42%), followed by that linked to the SPG3A locus on chromosome 14q11-q21 (in approximately 9%) [8].
  • Among the four loci causing AD-HSP identified so far, the SPG4 locus at chromosome 2p2-1p22 has been shown to account for 40-50% of all AD-HSP families [9].
  • Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia [9].
  • The sequence homologies and putative subcellular localization of spastin suggest that this ATPase is involved in the assembly or function of nuclear protein complexes [9].

Chemical compound and disease context of SPAST


Biological context of SPAST

  • The phenotype was compared with 126 SPG4 patients [2].
  • MAIN OUTCOME MEASURES: Mutations in the SPG4 and SPG3A genes as detected by direct sequencing of all coding exons and flanking intronic sequences [11].
  • A significant decrease in mitochondrial respiratory chain complexes I and IV was demonstrated in the non-SPG4/SPG7 group [12].
  • RESULTS:The genomic sequence of SPAST showed a heterozygous four--base pair deletion (delTAAT) near the 3' splice-site of exon three in all 11 affected individuals but not in 21 normal family members or in 50 unrelated controls (100 chromosomes) [13].
  • We used linkage information from several different research teams to evaluate the statistical probability of linkage to the SPG4 locus for uncomplicated AD HSP families and established the critical LOD-score value necessary for confirmation of linkage to the SPG4 locus from Bayesian statistics [14].

Anatomical context of SPAST


Associations of SPAST with chemical compounds

  • SSCP/sequencing analysis of the spastin gene showed a single base pair deletion causing a frame-shift in one family (1442delT) and a missense mutation (1726T>C) resulting in a leucine to proline amino-acid change (L534P) in the other family [18].
  • Cdk1 and Cdk5 showed no kinase activity toward synthetic spastin peptide in an in vitro kinase assay, suggesting that this serine residue may be phosphorylated by a different Cdk [19].
  • The CAG repeat expansion is very likely translated and expressed as indicated by the detection of a polyglutamine-containing protein in an ADPSP patient [20].
  • The most common form of HSP is caused by mutations in the SPG4 gene, which codes for spastin, an adenosine triphosphatase with various cellular activities (AAA) protein family member [21].

Physical interactions of SPAST

  • We show that the spastin domain required for binding to atlastin lies within the N-terminal 80 residues of the protein, a region that is only present in the predominantly cytoplasmic, full-length spastin isoform [22].
  • Using in vitro and in vivo immunoprecipitation experiments, we were able to demonstrate that RTN1 interacts specifically with spastin [23].

Other interactions of SPAST


Analytical, diagnostic and therapeutic context of SPAST


  1. High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia. Beetz, C., Nygren, A.O., Schickel, J., Auer-Grumbach, M., B??rk, K., Heide, G., Kassubek, J., Klimpe, S., Klopstock, T., Kreuz, F., Otto, S., Sch??le, R., Sch??ls, L., Sperfeld, A.D., Witte, O.W., Deufel, T. Neurology (2006) [Pubmed]
  2. Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia. Dürr, A., Camuzat, A., Colin, E., Tallaksen, C., Hannequin, D., Coutinho, P., Fontaine, B., Rossi, A., Gil, R., Rousselle, C., Ruberg, M., Stevanin, G., Brice, A. Arch. Neurol. (2004) [Pubmed]
  3. Spastin and paraplegin gene analysis in selected cases of motor neurone disease (MND). McDermott, C.J., Roberts, D., Tomkins, J., Bushby, K.M., Shaw, P.J. Amyotroph. Lateral Scler. Other Motor Neuron Disord. (2003) [Pubmed]
  4. Spastin mutations in sporadic adult-onset upper motor neuron syndromes. Brugman, F., Wokke, J.H., Scheffer, H., Versteeg, M.H., Sistermans, E.A., van den Berg, L.H. Ann. Neurol. (2005) [Pubmed]
  5. A cryptic promoter in the first exon of the SPG4 gene directs the synthesis of the 60-kDa spastin isoform. Mancuso, G., Rugarli, E.I. BMC Biol. (2008) [Pubmed]
  6. Mapping of a complicated familial spastic paraplegia to locus SPG4 on chromosome 2p. Heinzlef, O., Paternotte, C., Mahieux, F., Prud'homme, J.F., Dien, J., Madigand, M., Pouget, J., Weissenbach, J., Roullet, E., Hazan, J. J. Med. Genet. (1998) [Pubmed]
  7. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Patel, H., Cross, H., Proukakis, C., Hershberger, R., Bork, P., Ciccarelli, F.D., Patton, M.A., McKusick, V.A., Crosby, A.H. Nat. Genet. (2002) [Pubmed]
  8. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C.H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., Bui, M., Fink, J.K. Nat. Genet. (2001) [Pubmed]
  9. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Hazan, J., Fonknechten, N., Mavel, D., Paternotte, C., Samson, D., Artiguenave, F., Davoine, C.S., Cruaud, C., Dürr, A., Wincker, P., Brottier, P., Cattolico, L., Barbe, V., Burgunder, J.M., Prud'homme, J.F., Brice, A., Fontaine, B., Heilig, B., Weissenbach, J. Nat. Genet. (1999) [Pubmed]
  10. Three novel mutations of the spastin gene in Chinese patients with hereditary spastic paraplegia. Tang, B., Zhao, G., Xia, K., Pan, Q., Luo, W., Shen, L., Long, Z., Dai, H., Zi, X., Jiang, H. Arch. Neurol. (2004) [Pubmed]
  11. Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia. Park, S.Y., Ki, C.S., Kim, H.J., Kim, J.W., Sung, D.H., Kim, B.J., Lee, W.Y. Arch. Neurol. (2005) [Pubmed]
  12. Investigation of mitochondrial function in hereditary spastic paraparesis. McDermott, C.J., Taylor, R.W., Hayes, C., Johnson, M., Bushby, K.M., Turnbull, D.M., Shaw, P.J. Neuroreport (2003) [Pubmed]
  13. An atypical intronic deletion widens the spectrum of mutations in hereditary spastic paraplegia. Higgins, J.J., Loveless, J.M., Goswami, S., Nee, L.E., Cozzo, C., De Biase, A., Rosen, D.R. Neurology (2001) [Pubmed]
  14. Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait. Dubé, M.P., Mlodzienski, M.A., Kibar, Z., Farlow, M.R., Ebers, G., Harper, P., Kolodny, E.H., Rouleau, G.A., Figlewicz, D.A. Am. J. Hum. Genet. (1997) [Pubmed]
  15. Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Errico, A., Ballabio, A., Rugarli, E.I. Hum. Mol. Genet. (2002) [Pubmed]
  16. Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus. Charvin, D., Cifuentes-Diaz, C., Fonknechten, N., Joshi, V., Hazan, J., Melki, J., Betuing, S. Hum. Mol. Genet. (2003) [Pubmed]
  17. The hereditary spastic paraplegia protein spastin interacts with the ESCRT-III complex-associated endosomal protein CHMP1B. Reid, E., Connell, J., Edwards, T.L., Duley, S., Brown, S.E., Sanderson, C.M. Hum. Mol. Genet. (2005) [Pubmed]
  18. Novel spastin mutations and their expression analysis in two Italian families. Molon, A., Montagna, P., Angelini, C., Pegoraro, E. Eur. J. Hum. Genet. (2003) [Pubmed]
  19. Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. Svenson, I.K., Kloos, M.T., Gaskell, P.C., Nance, M.A., Garbern, J.Y., Hisanaga, S., Pericak-Vance, M.A., Ashley-Koch, A.E., Marchuk, D.A. Neurogenetics (2004) [Pubmed]
  20. CAG repeat expansion in autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24. Nielsen, J.E., Koefoed, P., Abell, K., Hasholt, L., Eiberg, H., Fenger, K., Niebuhr, E., Sørensen, S.A. Hum. Mol. Genet. (1997) [Pubmed]
  21. Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia. Meijer, I.A., Hand, C.K., Cossette, P., Figlewicz, D.A., Rouleau, G.A. Arch. Neurol. (2002) [Pubmed]
  22. Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners. Sanderson, C.M., Connell, J.W., Edwards, T.L., Bright, N.A., Duley, S., Thompson, A., Luzio, J.P., Reid, E. Hum. Mol. Genet. (2006) [Pubmed]
  23. Spastin, the most commonly mutated protein in hereditary spastic paraplegia interacts with Reticulon 1 an endoplasmic reticulum protein. Mannan, A.U., Boehm, J., Sauter, S.M., Rauber, A., Byrne, P.C., Neesen, J., Engel, W. Neurogenetics (2006) [Pubmed]
  24. Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance. Evans, K., Keller, C., Pavur, K., Glasgow, K., Conn, B., Lauring, B. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  25. CAG repeat expansion in autosomal dominant familial spastic paraparesis: novel expansion in a subset of patients. Benson, K.F., Horwitz, M., Wolff, J., Friend, K., Thompson, E., White, S., Richards, R.I., Raskind, W.H., Bird, T.D. Hum. Mol. Genet. (1998) [Pubmed]
  26. Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees in northeast England. McDermott, C.J., Dayaratne, R.K., Tomkins, J., Lusher, M.E., Lindsey, J.C., Johnson, M.A., Casari, G., Turnbull, D.M., Bushby, K., Shaw, P.J. Neurology (2001) [Pubmed]
  27. The cellular and molecular pathology of the motor system in hereditary spastic paraparesis due to mutation of the spastin gene. Wharton, S.B., McDermott, C.J., Grierson, A.J., Wood, J.D., Gelsthorpe, C., Ince, P.G., Shaw, P.J. J. Neuropathol. Exp. Neurol. (2003) [Pubmed]
  28. The identification of a conserved domain in both spartin and spastin, mutated in hereditary spastic paraplegia. Ciccarelli, F.D., Proukakis, C., Patel, H., Cross, H., Azam, S., Patton, M.A., Bork, P., Crosby, A.H. Genomics (2003) [Pubmed]
  29. Two novel mutations in the spastin gene (SPG4) found by DHPLC mutation analysis. Falco, M., Scuderi, C., Musumeci, S., Sturnio, M., Neri, M., Bigoni, S., Caniatti, L., Fichera, M. Neuromuscul. Disord. (2004) [Pubmed]
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