Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control.
Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control.
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DOI：
10.1136/jmg.2008.063917
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发表时间：
2009-06
影响因子：
4
通讯作者：
Scholz SW
中科院分区：
文献类型：
--
作者：
Brooks J;Ding J;Simon-Sanchez J;Paisan-Ruiz C;Singleton AB;Scholz SW
parkin和PTEN诱导的蛋白激酶（PINK 1）突变是常染色体隐性遗传性帕金森综合征的两个最常见的原因。这些基因中的杂合突变也有可能易患疾病或降低疾病发作的年龄，但目前还没有足够的数据来最终验证这一假设。研究parkin和PINK 1基因突变的频率和谱，并探讨杂合突变作为早发性帕金森病（PD）危险因素的作用。对250例早发性PD患者和276例正常对照者的PINK 1和parkin基因的所有外显子和外显子-内含子边界进行测序。基因剂量测量也进行了，使用高密度单核苷酸多态性阵列。总共发现了41种变异体，其中8种以前没有描述过（parkin：p.A38VfsX6，P.C166Y，P.Q171X，p.D243N，p.M458L; PINK 1：p.P52L，P.T420T，P.A427E）。1.60%的患者为致病突变纯合子或复合杂合子。与健康对照组相比，患者中致病性parkin或PINK 1突变的杂合性过高（4.00% vs. 1.81%），但差异不显著（p = 0.13）。纯合或复合杂合突变患者的平均发病年龄显著低于杂合突变患者（平均差异11岁，95% CI 1.4 - 20.6，p = 0.03）。与没有parkin或PINK 1突变的患者相比，杂合子患者的平均发病年龄没有显着差异（平均差异2年，95%CI-3.7至7.0，p = 0.54）。我们的数据支持与正常对照组相比，患者中致病性parkin或PINK 1突变的杂合性频率更高的趋势，但这种影响很小，在我们的250例病例和276例对照组中没有达到显著性。
Mutations in parkin and PTEN-induced protein kinase (PINK1) represent the two most common causes of autosomal recessive parkinsonism. The possibility that heterozygous mutations in these genes also predispose to disease or lower the age of disease onset has been suggested, but currently there is insufficient data to verify this hypothesis conclusively. To study the frequency and spectrum of parkin and PINK1 gene mutations and to investigate the role of heterozygous mutations as a risk factor for early-onset Parkinson’s disease (PD). All exons and exon-intron boundaries of PINK1 and parkin were sequenced in 250 patients with early-onset PD and 276 normal controls. Gene dosage measurements were also performed, using high-density single-nucleotide polymorphism arrays. In total 41 variants were found, of which 8 have not been previously described (parkin: p.A38VfsX6, P.C166Y, P.Q171X, p.D243N, p.M458L; PINK1: p.P52L, P.T420T, P.A427E). 1.60% of patients were homozygous or compound heterozygous for pathogenic mutations. Heterozygosity for pathogenic parkin or PINK1 mutations was over-represented in patients compared with healthy controls (4.00% vs. 1.81%) but the difference was not significant (p = 0.13). The mean age at disease onset was significantly lower in patients with homozygous or compound heterozygous mutations than in patients with heterozygous mutations (mean difference 11 years, 95% Cl 1.4 to 20.6, p = 0.03). There was no significant difference in the mean age at disease onset in heterozygous patients compared with patients without a mutation in parkin or PINK1 (mean difference 2 years, 95% Cl −3.7 to 7.0, p = 0.54). Our data support a trend towards a higher frequency of heterozygosity for pathogenic parkin or PINK1 mutations in patients compared with normal controls, but this effect was small and did not reach significance in our cohort of 250 cases and 276 controls.