Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans
Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans
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DOI：
10.1093/hmg/ddq081
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发表时间：
2010-05-15
影响因子：
3.5
通讯作者：
Brice, Alexis
中科院分区：
文献类型：
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作者：
Lesage, Suzanne;Patin, Etienne;Brice, Alexis
富含亮氨酸重复序列激酶2（LRRK 2）基因突变已在常染色体显性遗传帕金森病（PD）家族和散发病例中发现; G2019 S突变是最常见的单一突变。有趣的是，这种突变在PD患者中的频率在种族和地理来源之间差异很大：东亚患者中的突变率< 0.1%，欧洲血统患者中的突变率为2%，在PD德系犹太人和北非阿拉伯人中的突变率高达15-40%。为了确定G2019 S突变在不同人群中的进化动力学，我们对来自126个不同起源家庭的191个携带G2019 S突变的个体中跨越G2019 S周围16 Mb基因组区域的74个标记进行了基因分型。67个家庭为北非阿拉伯血统，18个家庭为北欧/西欧血统，37个家庭为犹太血统，大多数来自东欧，一个家庭来自日本，一个家庭来自土耳其，两个家庭为混合血统。我们在三种不同的单倍型上发现了G2019 S突变。对三种载体单倍型的网络分析表明，G2019 S在人类中独立出现至少两次。此外，最广泛的载体单倍型的等位基因内多样性的人口分布，以及通过两种不同方法确定的G2019 S年龄的估计，表明G2019 S突变事件之一至少发生在4000年前的近东。
Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (PD) and in sporadic cases; the G2019S mutation is the single most frequent. Intriguingly, the frequency of this mutation in PD patients varies greatly among ethnic groups and geographic origins: it is present at < 0.1% in East Asia, similar to 2% in European-descent patients and can reach frequencies of up to 15-40% in PD Ashkenazi Jews and North African Arabs. To ascertain the evolutionary dynamics of the G2019S mutation in different populations, we genotyped 74 markers spanning a 16 Mb genomic region around G2019S, in 191 individuals carrying the mutation from 126 families of different origins. Sixty-seven families were of North-African Arab origin, 18 were of North/Western European descent, 37 were of Jewish origin, mostly from Eastern Europe, one was from Japan, one from Turkey and two were of mixed origins. We found the G2019S mutation on three different haplotypes. Network analyses of the three carrier haplotypes showed that G2019S arose independently at least twice in humans. In addition, the population distribution of the intra-allelic diversity of the most widespread carrier haplotype, together with estimations of the age of G2019S determined by two different methods, suggests that one of the founding G2019S mutational events occurred in the Near East at least 4000 years ago.