Department of Medical Genetics, University of Tuebingen, Calwerstr 7, Tuebingen, 72076, Germany.
BMC Med Genet. 2012 Jun 21;13:48. doi: 10.1186/1471-2350-13-48.
Huntington disease (HD) is caused by an expanded CAG repeat in the HD gene. Although the length of the CAG repeat strongly correlates with the age-at-onset (AAO), AAO in HD individuals may differ dramatically in spite of similar expanded CAG repeat lengths. Additional genetic or environmental factors are thought to influence the disease onset. Several modifier genes have been discovered so far but they do not fully explain the variability of AAO in HD. To potentially identify a novel genetic modifier, we analyzed single nucleotide polymorphisms (SNPs) in the kalirin (KALRN) gene. Kalirin is a protein crucially involved in spine plasticity and its interaction with huntingtin-associated protein-1 (HAP-1) and a potential protein dysfunction might contribute to spine pathogenesis in HD.
The selected SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and association of SNPs with AAO was investigated with the framework of linear models in an analysis of variance and covariance.
Eleven SNPs in the kalirin gene were examined in an association study in European HD patients. The ten coding SNPs under investigation were monomorphic, whereas SNP rs10934657 in the promoter region showed a minor allele frequency >1%. An analysis of covariance together with the influence of the expanded HD allele was applied in 680 HD patients. SNP rs10934657 did not affect the AAO of the examined HD population.
The results did not reveal an association between the analyzed kalirin polymorphisms and the AAO in HD. However, it does not exclude other SNPs of the kalirin gene as susceptible genetic modifiers.
亨廷顿病（HD）是由 HD 基因中 CAG 重复扩增引起的。尽管 CAG 重复的长度与发病年龄（AAO）密切相关，但具有相似扩展 CAG 重复长度的 HD 个体的 AAO 可能存在显著差异。其他遗传或环境因素被认为会影响疾病的发病。到目前为止，已经发现了几个修饰基因，但它们并不能完全解释 HD 中 AAO 的可变性。为了潜在地鉴定新的遗传修饰因子，我们分析了 kalirin（KALRN）基因中的单核苷酸多态性（SNP）。Kalirin 是一种对脊柱可塑性至关重要的蛋白质，它与 huntingtin 相关蛋白-1（HAP-1）相互作用，其潜在的蛋白质功能障碍可能导致 HD 中的脊柱发病机制。
通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）对选定的 SNP 进行基因分型，并通过方差分析和协方差的线性模型框架研究 SNP 与 AAO 的关联。
在一项对欧洲 HD 患者的关联研究中，研究了 kalirin 基因中的 11 个 SNP。在所研究的 10 个编码 SNP 中，只有 SNP rs10934657 位于启动子区域，其次要等位基因频率>1%。在 680 名 HD 患者中应用协方差分析以及扩展的 HD 等位基因的影响。SNP rs10934657 并未影响所研究的 HD 人群的 AAO。
结果并未显示分析的 kalirin 多态性与 HD 中的 AAO 之间存在关联。然而，这并不排除 kalirin 基因的其他 SNP 作为易感遗传修饰因子。
