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. 2004 Sep;5(3):157-64.
doi: 10.1007/s10048-004-0186-z. Epub 2004 Jul 10.

Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations

Ingrid K Svenson  1 , 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
Affiliations

Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations

Ingrid K Svenson et al. Neurogenetics. 2004 Sep.

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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