Comprehensive mutational analysis of LRRK2 reveals variants supporting association with autosomal dominant Parkinson's disease
Comprehensive mutational analysis of LRRK2 reveals variants supporting association with autosomal dominant Parkinson's disease
复制标题
LRRK2 的综合突变分析揭示了支持常染色体显性帕金森病关联的变异
作者：
Yamashita T;Deguchi K;Nagotani S;Kamiya T;Abe K;Seki N
帕金森病（Parkinson's disease，PD）是一种以神经变性为特征的神经退行性疾病，最显著的是黑质中多巴胺能神经元的变性。到目前为止，已经确定了六个致病基因，包括LRRK 2，其突变在常染色体显性PD（Ad-PD）中最常见。我们对30例Ad-PD患者的LRRK 2基因进行了全面的突变分析，（11个日本人和19个高加索人）家庭采用基于DNA微阵列的重测序系统和直接核苷酸序列分析，并鉴定了23个变体，包括两个已知的突变，p.G2019S和p.I1371V，分别在三个高加索人家庭和一个高加索人家庭中，一个新的推定致病突变，p.N1221K，在一个日本家庭，和一个已知的非同义变体，p.G2385R，在两个日本家庭。对100例日本Ad-PD、73例散发性PD（sPD）和238例对照中p.G2385R的频率进行详细分析，结果显示Ad-PD中p.G2385R变异的频率显著高于对照（等位基因频率，9.0 vs 2.1%）（χ 2= 16.32，P= 5.34× 10− 5）。然而，p.G2385R变体没有显示出与PD的完全共分离。此外，p.G2385R等位基因频率在sPD组也高于对照组，但差异无统计学意义（等位基因频率分别为3.4%和2.1%）（χ 2= 0.76，P= 0.38）。这些观察结果支持p.G2385R与PD风险增加相关的可能性。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by neurodegeneration, most notably of dopaminergic neurons in the substantia nigra. To date, six causative genes have been identified including LRRK2, whose mutations are the most frequent in autosomal dominant PD (Ad-PD). We conducted a comprehensive mutational analysis of LRRK2 in 30 Ad-PD (11 Japanese and 19 Caucasian) families employing a DNA microarray-based resequencing system and direct nucleotide sequence analysis, and identified 23 variants including two known mutations, p. G2019S and p. I1371V, in three Caucasian families and one Caucasian family, respectively, a novel putative pathogenic mutation, p. N1221K, in one Japanese family, and a known nonsynonymous variant, p. G2385R, in two Japanese families. Detailed analysis of the frequency of p. G2385R among 100 Japanese Ad-PD, 73 sporadic PD (sPD) and 238 controls revealed that the frequency of the p. G2385R variant was significantly higher in Ad-PD than in controls (allele frequency, 9.0 vs 2.1%)(χ 2= 16.32, P= 5.34× 10− 5). The p. G2385R variant, however, did not show complete cosegregation with PD. In addition, the frequency of p. G2385R was also higher in sPD than in controls, although not significant (allele frequency, 3.4 vs 2.1%)(χ 2= 0.76, P= 0.38). These observations support the possibility that p. G2385R is associated with an increased risk of PD.