Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations
Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations
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DOI：
10.1007/s10048-004-0186-z
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发表时间：
2004-09-01
期刊：
影响因子：
2.2
通讯作者：
Marchuk, DA
中科院分区：
文献类型：
--
作者：
Svenson, IK;Kloos, MT;Marchuk, DA
遗传性痉挛性截瘫（HSP）是一种遗传异质性神经退行性疾病，其特征是家族内部和家族之间表型表达的广泛变异性。常染色体显性HSP的最常见原因是编码spastin的基因突变，spastin是一种功能不确定的蛋白质。我们报告了 spastin 基因内多态性的存在，它改变了 HSP 表型。一个（S44L）是先前描述的隐性作用等位基因，第二个是影响相邻氨基酸残基（P45Q）的新等位基因。在4个HSP家族中，L44或Q45独立于spastin AAA结构域中的错义或剪接突变而分离，在AAA结构域突变存在的情况下，L44和Q45各自与发病年龄的显着降低相关。使用生物信息学方法，我们发现高度保守的 S44 预计会被脯氨酸导向的丝氨酸/苏氨酸细胞周期蛋白依赖性激酶 (Cdks) 的许多家族成员磷酸化。在体外激酶测定中，Cdk1 和 Cdk5 对合成 spastin 肽没有表现出激酶活性，表明该丝氨酸残基可能被不同的 Cdk 磷酸化。我们将 S44L 和 P45Q 鉴定为 HSP 表型的修饰剂，表明 Cdks 磷酸化 spastin 在最常见形式的 HSP 神经变性中的作用。
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.