Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations

Ingrid K. Svenson, Mark T. Kloos, P. Craig Gaskell, Martha A. Nance, James Y. Garbern, Shin Ichi Hisanaga, Margaret A. Pericak-Vance, Allison E. Ashley-Koch, Douglas A. Marchuk

Research output: Contribution to journalArticle

62 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)157-164
Number of pages8
JournalNeurogenetics
Volume5
Issue number3
DOIs
StatePublished - Sep 1 2004
Externally publishedYes

Keywords

  • Cyclin-dependent kinases
  • Hereditary spastic paraplegia
  • Spastin

ASJC Scopus subject areas

  • Genetics(clinical)
  • Neuroscience(all)

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    Svenson, I. K., Kloos, M. T., Gaskell, P. C., Nance, M. A., Garbern, J. Y., Hisanaga, S. I., Pericak-Vance, M. A., Ashley-Koch, A. E., & Marchuk, D. A. (2004). Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. Neurogenetics, 5(3), 157-164. https://doi.org/10.1007/s10048-004-0186-z