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Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations

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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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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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Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA

    Ingrid K. Svenson, Mark T. Kloos & Douglas A. Marchuk

  2. Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA

    P. Craig Gaskell, Margaret A. Pericak-Vance & Allison E. Ashley-Koch

  3. Park Nicollet Clinic, Minneapolis, MN 55415, USA

    Martha A. Nance

  4. Department of Neurology, Wayne State University School of Medicine, Detroit Medical Center, Detroit, MI 48201, USA

    James Y. Garbern

  5. Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Hachiohji, Tokyo 192–0397, Japan

    Shin-ichi Hisanaga

  6. Duke University Medical Center, 265 CARL Building, Research Drive, Box 3175, Durham, NC 27710, USA

    Douglas A. Marchuk

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  1. Ingrid K. Svenson
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Correspondence to Douglas A. Marchuk.

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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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