Lange Lara M, Levine Kristin, Fox Susan H, Marras Connie, Ahmed Nazish, Kuznetsov Nicole, Vitale Dan, Iwaki Hirotaka, Lohmann Katja, Marsili Luca, Espay Alberto J, Bauer Peter, Beetz Christian, Martin Jessica, Factor Stewart A, Higginbotham Lenora A, Chen Honglei, Leonard Hampton, Nalls Mike, Mencacci Niccolo E, Morris Huw R, Klein Christine, Blauwendraat Cornelis, Fang Zih-Hua
Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
Department of Neurology, University Hospital Schleswig-Holstein, Luebeck, Germany.
Res Sq. 2024 Sep 20:rs.3.rs-4772543. doi: 10.21203/rs.3.rs-4772543/v1.
Pathogenic variants in the gene represent the most common cause of autosomal dominant Parkinson's disease (PD) worldwide. We identified the p.L1795F variant in 14 White/European ancestry PD patients, including two families with multiple affected carriers and seven additional affected individuals with familial PD using genotyping and sequencing data from more than 50,000 individuals through GP2, AMP-PD, PDGENEration, and CENTOGENE. All variant carriers were of White/European ancestry, and those with available genotyping data shared a common haplotype. The clinical presentation of p.L1795F carriers resembles that of other pathogenic variant carriers. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, our findings provide conclusive evidence that the p.L1795F variant is pathogenic. It represents a rare cause of PD in the European population but needs to be included in genetic testing efforts and considered for ongoing gene-specific clinical trials.
该基因中的致病变异是全球常染色体显性帕金森病（PD）最常见的病因。我们通过GP2、AMP-PD、PDGENEration和CENTOGENE，利用来自50000多名个体的基因分型和测序数据，在14名白种人/欧洲血统的帕金森病患者中鉴定出p.L1795F变异，其中包括两个有多名患病携带者的家族以及另外7名家族性帕金森病患者。所有变异携带者均为白种人/欧洲血统，那些有可用基因分型数据的携带者共享一个单倍型。p.L1795F携带者的临床表现与其他致病变异携带者相似。结合已发表的功能证据表明LRRK2激酶活性显著增强，我们的研究结果提供了确凿证据，证明p.L1795F变异是致病的。它是欧洲人群中帕金森病的罕见病因，但需要纳入基因检测工作，并在正在进行的基因特异性临床试验中予以考虑。
