title: Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations.
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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Ingrid K
authors.initials: IK
authors.lastname: Svenson
authors.forename: Mark T
authors.initials: MT
authors.lastname: Kloos
authors.forename: P Craig
authors.initials: PC
authors.lastname: Gaskell
authors.forename: Martha A
authors.initials: MA
authors.lastname: Nance
authors.forename: James Y
authors.initials: JY
authors.lastname: Garbern
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hisanaga
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Allison E
authors.initials: AE
authors.lastname: Ashley-Koch
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D017398:Alternative Splicing; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004252:DNA Mutational Analysis; D005091:Exons; D005192:Family Health; D005260:Female; D006801:Humans; D007438:Introns; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000737:chemistry; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D000074181:Spastin
chemical_list: D010455:Peptides; D012694:Serine; D051360:Cyclin-Dependent Kinase 5; D016203:CDC2 Protein Kinase; C495905:CDK5 protein, human; D018844:Cyclin-Dependent Kinases; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human