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- Title
Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations.
- Authors
Svenson, Ingrid K.; Kloos, Mark T.; Gaskell, P. Craig; Nance, Martha A.; Garbern, James Y.; Hisanaga, Shin-ichi; Pericak-Vance, Margaret A.; Ashley-Koch, Allison E.; Marchuk, Douglas A.
- 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 bio-informatics 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.
- Subjects
PARAPLEGIA; PARALYSIS; BRAIN diseases; NEURODEGENERATION; MEDICAL genetics
- Publication
Neurogenetics, 2004, Vol 5, Issue 3, p157
- ISSN
1364-6745
- Publication type
Article
- DOI
10.1007/s10048-004-0186-z