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Gene Review

ATL1  -  atlastin GTPase 1

Homo sapiens

Synonyms: AD-FSP, Atlastin-1, Brain-specific GTP-binding protein, FSP1, GBP-3, ...
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Disease relevance of SPG3A


High impact information on SPG3A

  • 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%) [6].
  • Fourth, in contrast to that seen in whites, the SNP ATL1 was in linkage equilibrium among African Americans, and it did not add new information to the STR haplotypes [7].
  • Haplotype and linkage analyses, with microsatellites covering the FSP region on chromosome 14q (locus FSP1), were performed [8].
  • In pedigree W, we found a haplotype that cosegregates with the disease and observed three crossing-over events, reducing the FSP1 candidate region to 7 cM; in addition, the observation of apparent anticipation in this family suggests a trinucleotide repeat expansion as the mutation [8].
  • SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development [9].

Chemical compound and disease context of SPG3A

  • We investigated the utility of fibroblast-specific protein 1 (FSP1), a member of the calmodulin S100 troponin C superfamily, for identifying lung fibroblasts in a murine model of pulmonary fibrosis induced by intratracheal administration of bleomycin [10].

Biological context of SPG3A


Anatomical context of SPG3A

  • The atlastin-1 protein is localized predominantly in brain, where it is enriched in pyramidal neurons in the cerebral cortex and hippocampus [1].
  • The atubular glomeruli were embedded in a dense interstitial matrix composed of cells positive for fibroblast (FSP-1) or macrophage (F4/80) markers, degenerated proximal tubules and collecting ducts, and diffuse fibrotic deposits [14].
  • In this study, we have investigated the mechanisms associated with human monocyte activation in response to 15-epi-16-(para-fluoro)-phenoxy-LXA4 (ATL-1), a stable 15-epi-LXA4 analog [15].
  • Together our results provide evidence that ATL-1 inhibits EC migration via the concerted inhibition of actin polymerization and proper assembly of focal adhesions, supporting a role for these novel lipid mediators as angiogenesis modulators [16].
  • In the present study, we investigated the effects of ATL-1 in the actin cytoskeleton reorganization of EC stimulated with VEGF [16].

Associations of SPG3A with chemical compounds


Physical interactions of SPG3A

  • 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 [18].

Regulatory relationships of SPG3A


Other interactions of SPG3A

  • By combining direct testing of SPAST and SPG3A, at least 50% of ADHSP families can now receive appropriate genetic diagnosis [20].
  • We propose that the KIF5A gene should be routinely analyzed in patients with hereditary spastic paraplegia negative for spastin and atlastin mutations [21].
  • METHODS: The SPG3A coding sequence was analyzed in DNA samples from the proband, her affected child, her unaffected parents, and control subjects by polymerase-chain-reaction amplification of each exon followed by direct DNA sequencing [4].
  • Pretreatment of EC with ATL-1 caused a reduction in VEGF-induced stress fibers and therefore reduced the intracellular content of filamentous actin [16].
  • We also examined the expression of fibroblast-specific protein-1 (FSP-1), which has been linked to epithelial-mesenchymal transition (EMT) and fibrosis, to determine whether it was linked to potential profibrotic and inflammatory FGF-1 mechanisms [22].

Analytical, diagnostic and therapeutic context of SPG3A

  • Yeast two-hybrid analyses and co-immunoprecipitation studies demonstrated that atlastin-1 can self-associate, and gel-exclusion chromatography and chemical cross-linking studies indicated that atlastin-1 exists as an oligomer in vivo, most likely a tetramer [1].
  • In cultured cortical neurons, atlastin-1 co-localized most prominently with markers of the Golgi apparatus, and immunogold electron microscopy revealed a predominant localization of atlastin-1 to the cis-Golgi [1].
  • Using confocal and electron microscopies, we have also found that atlastin-1 is highly enriched in vesicular structures within axonal growth cones and varicosities as well as at axonal branch points in cultured cerebral cortical neurons, prefiguring a functional role for atlastin-1 in axonal development [9].
  • Protein and mRNA expression of FSP1 was minimal in untreated lungs, but increased by 1 week after bleomycin administration and remained increased at 2 and 3 weeks after treatment [10].
  • In primary lung cell cultures, lung fibroblasts, but not macrophages or type II alveolar epithelial cells, expressed FSP1 [10].


  1. Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin. Zhu, P.P., Patterson, A., Lavoie, B., Stadler, J., Shoeb, M., Patel, R., Blackstone, C. J. Biol. Chem. (2003) [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. Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Bouslam, N., Benomar, A., Azzedine, H., Bouhouche, A., Namekawa, M., Klebe, S., Charon, C., Durr, A., Ruberg, M., Brice, A., Yahyaoui, M., Stevanin, G. Ann. Neurol. (2005) [Pubmed]
  4. De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. Rainier, S., Sher, C., Reish, O., Thomas, D., Fink, J.K. Arch. Neurol. (2006) [Pubmed]
  5. Characterization of a novel SPG3A deletion in a French-Canadian family. Meijer, I.A., Dion, P., Laurent, S., Dupré, N., Brais, B., Levert, A., Puymirat, J., Rioux, M.F., Sylvain, M., Zhu, P.P., Soderblom, C., Stadler, J., Blackstone, C., Rouleau, G.A. Ann. Neurol. (2007) [Pubmed]
  6. 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]
  7. Survey of the fragile X syndrome CGG repeat and the short-tandem-repeat and single-nucleotide-polymorphism haplotypes in an African American population. Crawford, D.C., Schwartz, C.E., Meadows, K.L., Newman, J.L., Taft, L.F., Gunter, C., Brown, W.T., Carpenter, N.J., Howard-Peebles, P.N., Monaghan, K.G., Nolin, S.L., Reiss, A.L., Feldman, G.L., Rohlfs, E.M., Warren, S.T., Sherman, S.L. Am. J. Hum. Genet. (2000) [Pubmed]
  8. Autosomal dominant familial spastic paraplegia: reduction of the FSP1 candidate region on chromosome 14q to 7 cM and locus heterogeneity. Gispert, S., Santos, N., Damen, R., Voit, T., Schulz, J., Klockgether, T., Orozco, G., Kreuz, F., Weissenbach, J., Auburger, G. Am. J. Hum. Genet. (1995) [Pubmed]
  9. SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development. Zhu, P.P., Soderblom, C., Tao-Cheng, J.H., Stadler, J., Blackstone, C. Hum. Mol. Genet. (2006) [Pubmed]
  10. Characterization of Fibroblast-specific Protein 1 in Pulmonary Fibrosis. Lawson, W.E., Polosukhin, V.V., Zoia, O., Stathopoulos, G.T., Han, W., Plieth, D., Loyd, J.E., Neilson, E.G., Blackwell, T.S. Am. J. Respir. Crit. Care Med. (2005) [Pubmed]
  11. SPG3A mutation screening in English families with early onset autosomal dominant hereditary spastic paraplegia. Wilkinson, P.A., Hart, P.E., Patel, H., Warner, T.T., Crosby, A.H. J. Neurol. Sci. (2003) [Pubmed]
  12. Novel mutation in the SPG3A gene in an African American family with an early onset of hereditary spastic paraplegia. Hedera, P., Fenichel, G.M., Blair, M., Haines, J.L. Arch. Neurol. (2004) [Pubmed]
  13. A founder effect and mutational hot spots may contribute to the most frequent mutations in the SPG3A gene. Namekawa, M., Nelson, I., Ribai, P., Dürr, A., Denis, E., Stevanin, G., Ruberg, M., Brice, A. Neurogenetics (2006) [Pubmed]
  14. Lack of endothelial nitric-oxide synthase leads to progressive focal renal injury. Forbes, M.S., Thornhill, B.A., Park, M.H., Chevalier, R.L. Am. J. Pathol. (2007) [Pubmed]
  15. Involvement of the Rho-kinase/myosin light chain kinase pathway on human monocyte chemotaxis induced by ATL-1, an aspirin-triggered lipoxin A4 synthetic analog. Simões, R.L., Fierro, I.M. J. Immunol. (2005) [Pubmed]
  16. Aspirin-triggered Lipoxin A4 inhibition of VEGF-induced endothelial cell migration involves actin polymerization and focal adhesion assembly. Cezar-de-Mello, P.F., Nascimento-Silva, V., Villela, C.G., Fierro, I.M. Oncogene (2006) [Pubmed]
  17. Fibroblast-specific protein 1 is a specific prognostic marker for renal survival in patients with IgAN. Nishitani, Y., Iwano, M., Yamaguchi, Y., Harada, K., Nakatani, K., Akai, Y., Nishino, T., Shiiki, H., Kanauchi, M., Saito, Y., Neilson, E.G. Kidney Int. (2005) [Pubmed]
  18. 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]
  19. Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells. Nascimento-Silva, V., Arruda, M.A., Barja-Fidalgo, C., Villela, C.G., Fierro, I.M. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  20. SPG3A: An additional family carrying a new atlastin mutation. Tessa, A., Casali, C., Damiano, M., Bruno, C., Fortini, D., Patrono, C., Cricchi, F., Valoppi, M., Nappi, G., Amabile, G.A., Bertini, E., Santorelli, F.M. Neurology (2002) [Pubmed]
  21. A missense mutation in the coiled-coil domain of the KIF5A gene and late-onset hereditary spastic paraplegia. Lo Giudice, M., Neri, M., Falco, M., Sturnio, M., Calzolari, E., Di Benedetto, D., Fichera, M. Arch. Neurol. (2006) [Pubmed]
  22. Immunolocalization of fibroblast growth factor-1 (FGF-1), its receptor (FGFR-1), and fibroblast-specific protein-1 (FSP-1) in inflammatory renal disease. Rossini, M., Cheunsuchon, B., Donnert, E., Ma, L.J., Thomas, J.W., Neilson, E.G., Fogo, A.B. Kidney Int. (2005) [Pubmed]
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