Early-onset parkinsonism associated with PINK1 mutations -: Frequency, genotypes, and phenotypes
Early-onset parkinsonism associated with PINK1 mutations -: Frequency, genotypes, and phenotypes
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DOI：
10.1212/01.wnl.0000167546.39375.82
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发表时间：
2005-07-12
期刊：
影响因子：
9.9
通讯作者：
Oostra, BA
中科院分区：
文献类型：
--
作者：
Bonifati, V;Rohé, CF;Oostra, BA
目的：评估早发性（<50岁）帕金森综合征患者中大量病例的PINK1基因突变的患病率、性质及相关表型。方法：作者研究了134例患者（116例散发，18例家族性；77%为意大利人）和90例意大利对照。从基因组DNA对PINK1基因的整个编码区进行测序；对选定病例分析互补DNA（cDNA）。结果：在90例意大利散发病例中有4例发现纯合致病性突变，包括新的谷氨酰胺456终止密码子（Gln456Stop）突变；在另外4例意大利散发病例中发现单个杂合截断或错义突变，包括两个新突变，脯氨酸196亮氨酸（Pro196Leu）和谷氨酰胺456终止密码子（Gln456Stop）突变。在家族性病例中未发现致病性突变。在病例和对照中发现新的（谷氨酰胺115亮氨酸，Gln115Leu）和已知的多态性频率相似。在携带单个杂合突变的病例中，cDNA分析未检测到其他突变，并揭示突变的C1366T/谷氨酰胺456终止密码子（Gln456Stop）等位基因在信使核糖核酸（mRNA）水平有主要致病作用。所有纯合突变患者发病极早，进展缓慢，对左旋多巴反应良好，包括一些患者起病对称、起病时有肌张力障碍以及睡眠改善，类似于帕金相关疾病。单个杂合突变患者的表型相似，但发病较晚。结论：PINK1纯合突变是意大利早发性帕金森综合征散发患者中疾病的一个相关病因。单个杂合状态下发现的突变的作用难以解释。我们的研究表明，至少在一些患者中，这些突变与其他仍未知的因素共同导致疾病。
Objective: To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset ( < 50 years) parkinsonism. Methods: The authors studied 134 patients ( 116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases. Results: Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to L-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later. Conclusions: PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.