Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Svenson, IK; Kloos, MT; Gaskell, PC; Nance, MA; Garbern, JY; Hisanaga, S-I; Pericak-Vance, MA; Ashley-Koch, AE; Marchuk, DA

Published Date

  • September 2004

Published In

Volume / Issue

  • 5 / 3

Start / End Page

  • 157 - 164

PubMed ID

  • 15248095

Pubmed Central ID

  • 15248095

International Standard Serial Number (ISSN)

  • 1364-6745

Digital Object Identifier (DOI)

  • 10.1007/s10048-004-0186-z

Language

  • eng

Conference Location

  • United States