| Structural highlights
Disease
[SPAST_HUMAN] Defects in SPAST are the cause of spastic paraplegia autosomal dominant type 4 (SPG4) [MIM:182601]. Spastic paraplegia is a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG4 is the most common form of autosomal dominant spastic paraplegias.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35]
Function
[SPAST_HUMAN] ATP-dependent microtubule severing protein. Microtubule severing may promote reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and for completion of the abscission stage of cytokinesis. May also play a role in axon growth and the formation of axonal branches.[36] [37] [38] [39] [40] [41]
References
- ↑ Errico A, Ballabio A, Rugarli EI. Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet. 2002 Jan 15;11(2):153-63. PMID:11809724
- ↑ Evans KJ, Gomes ER, Reisenweber SM, Gundersen GG, Lauring BP. Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing. J Cell Biol. 2005 Feb 14;168(4):599-606. PMID:15716377 doi:10.1083/jcb.200409058
- ↑ White SR, Evans KJ, Lary J, Cole JL, Lauring B. Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing. J Cell Biol. 2007 Mar 26;176(7):995-1005. PMID:17389232 doi:10.1083/jcb.200610072
- ↑ Connell JW, Lindon C, Luzio JP, Reid E. Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion. Traffic. 2009 Jan;10(1):42-56. doi: 10.1111/j.1600-0854.2008.00847.x. Epub 2008, Oct 29. PMID:19000169 doi:10.1111/j.1600-0854.2008.00847.x
- ↑ Sanderson CM, Connell JW, Edwards TL, Bright NA, Duley S, Thompson A, Luzio JP, Reid E. Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners. Hum Mol Genet. 2006 Jan 15;15(2):307-18. Epub 2005 Dec 8. PMID:16339213 doi:10.1093/hmg/ddi447
- ↑ Svenson IK, Kloos MT, Jacon A, Gallione C, Horton AC, Pericak-Vance MA, Ehlers MD, Marchuk DA. Subcellular localization of spastin: implications for the pathogenesis of hereditary spastic paraplegia. Neurogenetics. 2005 Sep;6(3):135-41. Epub 2005 Sep 28. PMID:15891913 doi:10.1007/s10048-005-0219-2
- ↑ Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, Davoine CS, Cruaud C, Durr A, Wincker P, Brottier P, Cattolico L, Barbe V, Burgunder JM, Prud'homme JF, Brice A, Fontaine B, Heilig B, Weissenbach J. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet. 1999 Nov;23(3):296-303. PMID:10610178 doi:10.1038/15472
- ↑ Burger J, Fonknechten N, Hoeltzenbein M, Neumann L, Bratanoff E, Hazan J, Reis A. Hereditary spastic paraplegia caused by mutations in the SPG4 gene. Eur J Hum Genet. 2000 Oct;8(10):771-6. PMID:11039577 doi:10.1038/sj.ejhg.5200528
- ↑ Fonknechten N, Mavel D, Byrne P, Davoine CS, Cruaud C, Bonsch D, Samson D, Coutinho P, Hutchinson M, McMonagle P, Burgunder JM, Tartaglione A, Heinzlef O, Feki I, Deufel T, Parfrey N, Brice A, Fontaine B, Prud'homme JF, Weissenbach J, Durr A, Hazan J. Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet. 2000 Mar 1;9(4):637-44. PMID:10699187
- ↑ Lindsey JC, Lusher ME, McDermott CJ, White KD, Reid E, Rubinsztein DC, Bashir R, Hazan J, Shaw PJ, Bushby KM. Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis. J Med Genet. 2000 Oct;37(10):759-65. PMID:11015453
- ↑ Hentati A, Deng HX, Zhai H, Chen W, Yang Y, Hung WY, Azim AC, Bohlega S, Tandan R, Warner C, Laing NG, Cambi F, Mitsumoto H, Roos RP, Boustany RM, Ben Hamida M, Hentati F, Siddique T. Novel mutations in spastin gene and absence of correlation with age at onset of symptoms. Neurology. 2000 Nov 14;55(9):1388-90. PMID:11087788
- ↑ Svenson IK, Ashley-Koch AE, Gaskell PC, Riney TJ, Cumming WJ, Kingston HM, Hogan EL, Boustany RM, Vance JM, Nance MA, Pericak-Vance MA, Marchuk DA. Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. Am J Hum Genet. 2001 May;68(5):1077-85. Epub 2001 Apr 16. PMID:11309678 doi:S0002-9297(07)61216-6
- ↑ Namekawa M, Takiyama Y, Sakoe K, Nagaki H, Shimazaki H, Yoshimura M, Ikeguchi K, Nakano I, Nishizawa M. A Japanese SPG4 family with a novel missense mutation of the SPG4 gene: intrafamilial variability in age at onset and clinical severity. Acta Neurol Scand. 2002 Dec;106(6):387-91. PMID:12460147
- ↑ Meijer IA, Hand CK, Cossette P, Figlewicz DA, Rouleau GA. Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia. Arch Neurol. 2002 Feb;59(2):281-6. PMID:11843700
- ↑ Sauter S, Miterski B, Klimpe S, Bonsch D, Schols L, Visbeck A, Papke T, Hopf HC, Engel W, Deufel T, Epplen JT, Neesen J. Mutation analysis of the spastin gene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia. Hum Mutat. 2002 Aug;20(2):127-32. PMID:12124993 doi:10.1002/humu.10105
- ↑ Yabe I, Sasaki H, Tashiro K, Matsuura T, Takegami T, Satoh T. Spastin gene mutation in Japanese with hereditary spastic paraplegia. J Med Genet. 2002 Aug;39(8):e46. PMID:12161613
- ↑ Patrono C, Casali C, Tessa A, Cricchi F, Fortini D, Carrozzo R, Siciliano G, Bertini E, Santorelli FM. Missense and splice site mutations in SPG4 suggest loss-of-function in dominant spastic paraplegia. J Neurol. 2002 Feb;249(2):200-5. PMID:11985387
- ↑ Proukakis C, Hart PE, Cornish A, Warner TT, Crosby AH. Three novel spastin (SPG4) mutations in families with autosomal dominant hereditary spastic paraplegia. J Neurol Sci. 2002 Sep 15;201(1-2):65-9. PMID:12163196
- ↑ Ki CS, Lee WY, Han DH, Sung DH, Lee KB, Lee KA, Cho SS, Cho S, Hwang H, Sohn KM, Choi YJ, Kim JW. A novel missense mutation (I344K) in the SPG4gene in a Korean family with autosomal-dominant hereditary spastic paraplegia. J Hum Genet. 2002;47(9):473-7. PMID:12202986 doi:10.1007/s100380200068
- ↑ Proukakis C, Auer-Grumbach M, Wagner K, Wilkinson PA, Reid E, Patton MA, Warner TT, Crosby AH. Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 (Spastin) gene. Hum Mutat. 2003 Feb;21(2):170. PMID:12552568 doi:10.1002/humu.9108
- ↑ Molon A, Montagna P, Angelini C, Pegoraro E. Novel spastin mutations and their expression analysis in two Italian families. Eur J Hum Genet. 2003 Sep;11(9):710-3. PMID:12939659 doi:https://dx.doi.org/10.1038/sj.ejhg.5201027
- ↑ Tang B, Zhao G, Xia K, Pan Q, Luo W, Shen L, Long Z, Dai H, Zi X, Jiang H. Three novel mutations of the spastin gene in Chinese patients with hereditary spastic paraplegia. Arch Neurol. 2004 Jan;61(1):49-55. PMID:14732620 doi:10.1001/archneur.61.1.49
- ↑ Orlacchio A, Kawarai T, Totaro A, Errico A, St George-Hyslop PH, Rugarli EI, Bernardi G. Hereditary spastic paraplegia: clinical genetic study of 15 families. Arch Neurol. 2004 Jun;61(6):849-55. PMID:15210521 doi:10.1001/archneur.61.6.849
- ↑ Svenson IK, Kloos MT, Gaskell PC, Nance MA, Garbern JY, Hisanaga S, Pericak-Vance MA, Ashley-Koch AE, Marchuk DA. Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. Neurogenetics. 2004 Sep;5(3):157-64. Epub 2004 Jul 10. PMID:15248095 doi:10.1007/s10048-004-0186-z
- ↑ Falco M, Scuderi C, Musumeci S, Sturnio M, Neri M, Bigoni S, Caniatti L, Fichera M. Two novel mutations in the spastin gene (SPG4) found by DHPLC mutation analysis. Neuromuscul Disord. 2004 Nov;14(11):750-3. PMID:15482961 doi:10.1016/j.nmd.2004.05.017
- ↑ Orlacchio A, Gaudiello F, Totaro A, Floris R, St George-Hyslop PH, Bernardi G, Kawarai T. A new SPG4 mutation in a variant form of spastic paraplegia with congenital arachnoid cysts. Neurology. 2004 May 25;62(10):1875-8. PMID:15159500
- ↑ Chinnery PF, Keers SM, Holden MJ, Ramesh V, Dalton A. Infantile hereditary spastic paraparesis due to codominant mutations in the spastin gene. Neurology. 2004 Aug 24;63(4):710-2. PMID:15326248
- ↑ Crippa F, Panzeri C, Martinuzzi A, Arnoldi A, Redaelli F, Tonelli A, Baschirotto C, Vazza G, Mostacciuolo ML, Daga A, Orso G, Profice P, Trabacca A, D'Angelo MG, Comi GP, Galbiati S, Lamperti C, Bonato S, Pandolfo M, Meola G, Musumeci O, Toscano A, Trevisan CP, Bresolin N, Bassi MT. Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. Arch Neurol. 2006 May;63(5):750-5. PMID:16682546 doi:63/5/750
- ↑ Magariello A, Muglia M, Patitucci A, Mazzei R, Conforti FL, Gabriele AL, Sprovieri T, Ungaro C, Gambardella A, Mancuso M, Siciliano G, Branca D, Aguglia U, de Angelis MV, Longo K, Quattrone A. Novel spastin (SPG4) mutations in Italian patients with hereditary spastic paraplegia. Neuromuscul Disord. 2006 Jun;16(6):387-90. Epub 2006 May 8. PMID:16684598 doi:10.1016/j.nmd.2006.03.009
- ↑ Erichsen AK, Inderhaug E, Mattingsdal M, Eiklid K, Tallaksen CM. Seven novel mutations and four exon deletions in a collection of Norwegian patients with SPG4 hereditary spastic paraplegia. Eur J Neurol. 2007 Jul;14(7):809-14. PMID:17594340 doi:10.1111/j.1468-1331.2007.01861.x
- ↑ Braschinsky M, Tamm R, Beetz C, Sachez-Ferrero E, Raukas E, Luus SM, Gross-Paju K, Boillot C, Canzian F, Metspalu A, Haldre S. Unique spectrum of SPAST variants in Estonian HSP patients: presence of benign missense changes but lack of exonic rearrangements. BMC Neurol. 2010 Mar 9;10:17. doi: 10.1186/1471-2377-10-17. PMID:20214791 doi:10.1186/1471-2377-10-17
- ↑ Alvarez V, Sanchez-Ferrero E, Beetz C, Diaz M, Alonso B, Corao AI, Gamez J, Esteban J, Gonzalo JF, Pascual-Pascual SI, Lopez de Munain A, Moris G, Ribacoba R, Marquez C, Rosell J, Marin R, Garcia-Barcina MJ, Del Castillo E, Benito C, Coto E. Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. BMC Neurol. 2010 Oct 8;10:89. doi: 10.1186/1471-2377-10-89. PMID:20932283 doi:10.1186/1471-2377-10-89
- ↑ de Bot ST, van den Elzen RT, Mensenkamp AR, Schelhaas HJ, Willemsen MA, Knoers NV, Kremer HP, van de Warrenburg BP, Scheffer H. Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations. J Neurol Neurosurg Psychiatry. 2010 Oct;81(10):1073-8. doi:, 10.1136/jnnp.2009.201103. Epub 2010 Jun 20. PMID:20562464 doi:10.1136/jnnp.2009.201103
- ↑ McCorquodale DS 3rd, Ozomaro U, Huang J, Montenegro G, Kushman A, Citrigno L, Price J, Speziani F, Pericak-Vance MA, Zuchner S. Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia. Clin Genet. 2011 Jun;79(6):523-30. doi: 10.1111/j.1399-0004.2010.01501.x. PMID:20718791 doi:10.1111/j.1399-0004.2010.01501.x
- ↑ Battini R, Fogli A, Borghetti D, Michelucci A, Perazza S, Baldinotti F, Conidi ME, Ferreri MI, Simi P, Cioni G. Clinical and genetic findings in a series of Italian children with pure hereditary spastic paraplegia. Eur J Neurol. 2011 Jan;18(1):150-7. doi: 10.1111/j.1468-1331.2010.03102.x. PMID:20550563 doi:10.1111/j.1468-1331.2010.03102.x
- ↑ Errico A, Ballabio A, Rugarli EI. Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet. 2002 Jan 15;11(2):153-63. PMID:11809724
- ↑ Ciccarelli FD, Proukakis C, Patel H, Cross H, Azam S, Patton MA, Bork P, Crosby AH. The identification of a conserved domain in both spartin and spastin, mutated in hereditary spastic paraplegia. Genomics. 2003 Apr;81(4):437-41. PMID:12676568
- ↑ Evans KJ, Gomes ER, Reisenweber SM, Gundersen GG, Lauring BP. Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing. J Cell Biol. 2005 Feb 14;168(4):599-606. PMID:15716377 doi:10.1083/jcb.200409058
- ↑ Salinas S, Carazo-Salas RE, Proukakis C, Cooper JM, Weston AE, Schiavo G, Warner TT. Human spastin has multiple microtubule-related functions. J Neurochem. 2005 Dec;95(5):1411-20. Epub 2005 Oct 7. PMID:16219033 doi:10.1111/j.1471-4159.2005.03472.x
- ↑ White SR, Evans KJ, Lary J, Cole JL, Lauring B. Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing. J Cell Biol. 2007 Mar 26;176(7):995-1005. PMID:17389232 doi:10.1083/jcb.200610072
- ↑ Connell JW, Lindon C, Luzio JP, Reid E. Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion. Traffic. 2009 Jan;10(1):42-56. doi: 10.1111/j.1600-0854.2008.00847.x. Epub 2008, Oct 29. PMID:19000169 doi:10.1111/j.1600-0854.2008.00847.x
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