Abstract
Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease characterized by wide variability in phenotypic expression, both within and among families. The most-common cause of autosomal dominant HSP is mutation of the gene encoding spastin, a protein of uncertain function. We report the existence of intragenic polymorphisms of spastin that modify the HSP phenotype. One (S44L) is a previously described recessively acting allele and the second is a novel allele affecting the adjacent amino acid residue (P45Q). In 4 HSP families in which either L44 or Q45 segregates independently of a missense or splicing mutation in the AAA domain of spastin, L44 and Q45 are each associated with a striking decrease in age at onset in the presence of the AAA domain mutations. Using a bioinformatics approach, we found that the highly conserved S44 is predicted to be phosphorylated by a number of family members of the proline-directed serine/threonine cyclin-dependent kinases (Cdks). 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. Our identification of S44L and P45Q as modifiers of the HSP phenotype suggests a role for spastin phosphorylation by Cdks in the neurodegeneration of the most-common form of HSP.
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References
Fink JK (1997) Advances in hereditary spastic paraplegia. Curr Opin Neurol 10:313–318
Reid E (2003) Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias. J Med Genet 40:81–86
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 (1999) Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet 23:296–303
Patel S, Latterich M (1998) The AAA team: related ATPases with diverse functions. Trends Cell Biol 8:65–71
Lupas AN, Martin J (2002) AAA proteins. Curr Opin Struct Biol 12:746–753
Lindsey JC, Lusher ME, McDermott CJ, White KD, Reid E, Rubinsztein DC, Bashir R, Hazan J, Shaw PJ, Bushby KM (2000) Mutation analysis of the spastin gene ( SPG4) in patients with hereditary spastic paraparesis. J Med Genet 37:759–765
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 (2001) Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. Am J Hum Genet 68:1077–1085
Saito T, Onuki R, Fujita Y, Kusakawa G, Ishiguro K, Bibb JA, Kishimoto T, Hisanaga S (2003) Developmental regulation of the proteolysis of the p35 cyclin-dependent kinase 5 activator by phosphorylation. J Neurosci 23:1189–1197
Yaffe MB, Leparc GG, Lai J, Obata T, Volinia S, Cantley LC (2001) A motif-based profile scanning approach for genome-wide prediction of signaling pathways. Nat Biotechnol 19:348–353
Takeda DY, Wohlschlegel JA, Dutta A (2001) A bipartite substrate recognition motif for cyclin-dependent kinases. J Biol Chem 276:1993–1997
Adams PD, Li X, Sellers WR, Baker KB, Leng X, Harper JW, Taya Y, Kaelin WG Jr (1999) Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes. Mol Cell Biol 19:1068–1080
Meijer IA, Hand CK, Cossette P, Figlewicz DA, Rouleau GA (2002) Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia. Arch Neurol 59:281–286
Fonknechten N, Mavel D, Byrne P, Davoine CS, Cruaud C, Boentsch 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 (2000) Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet 9:637–644
Svenson IK, Ashley-Koch AE, Pericak-Vance MA, Marchuk DA (2001) A second leaky splice-site mutation in the spastin gene. Am J Hum Genet 69:1407–1409
Fink JK (2002) Hereditary spastic paraplegia: the pace quickens. Ann Neurol 51:669–672
Mastrianni JA, Curtis MT, Oberholtzer JC, Da Costa MM, DeArmond S, Prusiner SB, Garbern JY (1995) Prion disease (PrP-A117 V) presenting with ataxia instead of dementia. Neurology 45:2042–2050
Petersen RB, Parchi P, Richardson SL, Urig CB, Gambetti P (1996) Effect of the D178 N mutation and the codon 129 polymorphism on the metabolism of the prion protein. J Biol Chem 271:12661–12668
Berr C, Helbecque N, Sazdovitch V, Mohr M, Amant C, Amouyel P, Alperovitch A, Hauw JJ (2003) Polymorphism of the codon 129 of the prion protein (PrP) gene and neuropathology of cerebral ageing. Acta Neuropathol (Berl) 106:71–74
Ben-Chetrit E, Lerer I, Malamud E, Domingo C, Abeliovich D (2000) The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant? Hum Mutat 15:385–386
Chillon M, Palacio A, Nunes V, Estivill X (1992) A rare DNA variant in exon 15 of the cystic fibrosis transmembrane conductance regulator ( CFTR) gene. Hum Genet 90:474
Kiesewetter S, Macek M Jr, Davis C, Curristin SM, Chu CS, Graham C, Shrimpton AE, Cashman SM, Tsui LC, Mickle J, et al (1993) A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet 5:274–278
Pagani F, Buratti E, Stuani C, Baralle FE (2003) Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9. J Biol Chem 278:26580–26588
Pagani F, Stuani C, Tzetis M, Kanavakis E, Efthymiadou A, Doudounakis S, Casals T, Baralle FE (2003) New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12. Hum Mol Genet 12:1111–1120
Rave-Harel N, Kerem E, Nissim-Rafinia M, Madjar I, Goshen R, Augarten A, Rahat A, Hurwitz A, Darvasi A, Kerem B (1997) The molecular basis of partial penetrance of splicing mutations in cystic fibrosis. Am J Hum Genet 60:87–94
Chiba-Falek O, Kerem E, Shoshani T, Aviram M, Augarten A, Bentur L, Tal A, Tullis E, Rahat A, Kerem B (1998) The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C-->T mutation. Genomics 53:276–283
Larriba S, Bassas L, Gimenez J, Ramos MD, Segura A, Nunes V, Estivill X, Casals T (1998) Testicular CFTR splice variants in patients with congenital absence of the vas deferens. Hum Mol Genet 7:1739–1743
Errico A, Ballabio A, Rugarli EI (2002) Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet 11:153–163
McDermott CJ, Grierson AJ, Wood JD, Bingley M, Wharton SB, Bushby KM, Shaw PJ (2003) Hereditary spastic paraparesis: disrupted intracellular transport associated with spastin mutation. Ann Neurol 54:748–759
Wu Y, Spencer SD, Lasky LA (1998) Tyrosine phosphorylation regulates the SH3-mediated binding of the Wiskott-Aldrich syndrome protein to PSTPIP, a cytoskeletal-associated protein. J Biol Chem 273:5765–5770
Hansen TO, Rehfeld JF, Nielsen FC (2000) Cyclic AMP-induced neuronal differentiation via activation of p38 mitogen-activated protein kinase. J Neurochem 75:1870–1877
Cavanaugh JE, Ham J, Hetman M, Poser S, Yan C, Xia Z (2001) Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. J Neurosci 21:434–443
Nguyen MD, Mushynski WE, Julien JP (2002) Cycling at the interface between neurodevelopment and neurodegeneration. Cell Death Differ 9:1294–1306
Veeranna, Amin ND, Ahn NG, Jaffe H, Winters CA, Grant P, Pant HC (1998) Mitogen-activated protein kinases (Erk1,2) phosphorylate Lys-Ser-Pro (KSP) repeats in neurofilament proteins NF-H and NF-M. J Neurosci 18:4008–4021
Illenberger S, Zheng-Fischhofer Q, Preuss U, Stamer K, Baumann K, Trinczek B, Biernat J, Godemann R, Mandelkow EM, Mandelkow E (1998) The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer’s disease. Mol Biol Cell 9:1495–1512
Smith D (2003) Cdk5 in neuroskeletal dynamics. Neurosignals 12:239–251
Reid E, Kloos M, Ashley-Koch A, Hughes L, Bevan S, Svenson IK, Graham FL, Gaskell PC, Dearlove A, Pericak-Vance MA, Rubinsztein DC, Marchuk DA (2002) A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet 71:1189–1194
Crosby AH, Proukakis C (2002) Is the transportation highway the right road for hereditary spastic paraplegia? Am J Hum Genet 71:1009–1016
Acknowledgements.
We thank the patients and their families for their participation. This work was supported by grant P01 NS26630 to M.P.V. I.K.S. is the recipient of a Ruth K. Broad Biomedical Research Foundation Fellowship Award.
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Svenson, I.K., Kloos, M.T., Gaskell, P.C. et al. Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. Neurogenetics 5, 157–164 (2004). https://doi.org/10.1007/s10048-004-0186-z
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DOI: https://doi.org/10.1007/s10048-004-0186-z