Di Fonzo Alessio, Tassorelli Cristina, De Mari Michele, Chien Hsin F, Ferreira Joaquim, Rohé Christan F, Riboldazzi Giulio, Antonini Angelo, Albani Gianni, Mauro Alessandro, Marconi Roberto, Abbruzzese Giovanni, Lopiano Leonardo, Fincati Emiliana, Guidi Marco, Marini Paolo, Stocchi Fabrizio, Onofrj Marco, Toni Vincenzo, Tinazzi Michele, Fabbrini Giovanni, Lamberti Paolo, Vanacore Nicola, Meco Giuseppe, Leitner Petra, Uitti Ryan J, Wszolek Zbigniew K, Gasser Thomas, Simons Erik J, Breedveld Guido J, Goldwurm Stefano, Pezzoli Gianni, Sampaio Cristina, Barbosa Egberto, Martignoni Emilia, Oostra Ben A, Bonifati Vincenzo
Department of Clinical Genetics, Erasmus MC Rotterdam, Rotterdam, The Netherlands.
Eur J Hum Genet. 2006 Mar;14(3):322-31. doi: 10.1038/sj.ejhg.5201539.
Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.
富含亮氨酸重复激酶2（LRRK2）基因的突变最近在帕金森病（PD）家族中被发现。然而，LRRK2突变的患病率和性质、该基因的多态性内容以及相关表型仍知之甚少。我们在大量符合常染色体显性遗传（ADPD）的帕金森病家族样本中对该基因进行了全面研究。通过基因组测序对60名ADPD先证者（83%为意大利人）的LRRK2基因全长开放阅读框和剪接位点（51个外显子）进行了研究。在6名先证者（10%）中发现了致病突变：4名（6.6%）为杂合子p.G2019S突变，2名（3.4%）先证者为杂合子p.R1441C突变。另一名先证者携带杂合子p.I1371V突变，但无法确定其致病作用。总共还鉴定了13个新的与疾病无关的变异和3个意义不确定的内含子变化。与LRRK2致病突变相关的表型是典型的帕金森病，但发病年龄范围广泛（平均55.2岁，范围38 - 68岁），并且在某些情况下疾病进展缓慢。基于对大量样本的全面研究，我们得出结论，致病的LRRK2突变在ADPD中很常见，并且它们聚集在编码蛋白的C端一半区域。这些数据对于理解帕金森病的分子机制以及指导临床实践中的基因筛查都具有重要意义。
