Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations Journal Article uri icon
  • 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.

  • Link to Article
    publication date
  • 2004
  • published in
  • Neurogenetics  Journal
  • Research
  • Adenosine Triphosphatases/*genetics
  • Adolescent
  • Alternative Splicing
  • CDC2 Protein Kinase/metabolism
  • Child
  • Computational Biology
  • Cyclin-Dependent Kinase 5
  • Cyclin-Dependent Kinases/metabolism
  • DNA Mutational Analysis
  • Exons
  • Family Health
  • Introns
  • Lymphocytes/metabolism
  • Mutation
  • Mutation, Missense
  • Pedigree
  • Peptides/chemistry
  • Phenotype
  • Phosphorylation
  • Polymorphism, Genetic
  • Protein Structure, Tertiary
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine/chemistry
  • Spastic Paraplegia, Hereditary/*genetics
  • Spastin
  • Additional Document Info
  • 5
  • issue
  • 3