Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease
Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease
复制标题
DOI：
10.1093/brain/awh666
复制
发表时间：
2005-12-01
期刊：
影响因子：
14.5
通讯作者：
Gasser, T
中科院分区：
文献类型：
--
作者：
Berg, D;Schweitzer, KJ;Gasser, T
越来越多的证据表明遗传因素对帕金森病的发病机制有影响。富含亮氨酸重复激酶 2 (LRRK2) 基因突变的鉴定为导致常染色体显性遗传帕金森病的遗传变异提供了新的线索。在这项迄今为止发表的最全面的分析中，我们通过直接测序对包含 53 个帕金森病家族的 LRRK2 基因突变进行了第二个大系列筛查，以进一步确定突变频率并评估临床表型，从而建立基因型/表型关系。为了进行比较，使用 ABI 7900 等位基因检测系统对 337 名明显散发性帕金森病患者和 1200 名对照受试者的队列中的所有新型和已知突变进行了研究。我们在 53 个患有帕金森病的家庭中又发现了 7 个具有 LRRK2 变异的家庭。其中四个是新的氨基酸取代（R793M、Q930R、S1096C、S1228T）。由于不完全外显率和可能的表型，无法确定 Q930R 和 S1096C 突变以及之前描述的 A3342G 剪接位点突变的致病相关性。在我们的大型队列中尚未检测到迄今为止最常见的突变（G2019）。通常观察到迟发型和典型的左旋多巴反应性帕金森病特征，常伴有执行功能损害和神经心理学测试中的高干扰值，以及睡眠障碍，但很少出现幻觉。电生理检查未见异常。可以观察到明显的家庭内和家庭间差异，包括一名患者弥漫性路易体病的临床表现。与特发性帕金森病经颅超声检查相比，MRI 常见的脑萎缩和黑质高回声较少，需要进一步研究证实。因此，结合我们第一项研究中在 46 个家庭中获得的结果，LRRK2 突变占我们人群中明显常染色体显性遗传家族的 13%，这些家族的帕金森病临床表现各不相同，但仍然普遍典型。
There is increasing evidence of genetic contribution to the pathogenesis of Parkinson's disease. The identification of mutations in the leucine-rich repeat kinase 2 (LRRK2) gene has shed new light on genetic variations responsible for autosomal dominantly inherited Parkinson's disease. In this analysis, the most comprehensive published so far, we screened a second large series comprising 53 families with Parkinson's disease for mutations in the LRRK2 gene by direct sequencing to further determine the frequency of the mutation and evaluate the clinical phenotype to establish a genotype/phenotype relation. For comparison, all novel and known mutations were investigated in a cohort of 337 patients with apparently sporadic Parkinson's disease and a cohort of 1200 control subjects using an ABI 7900 Allelic Detection system. We identified 7 more families with LRRK2 variations in the 53 families with Parkinson's disease. Four of these are novel amino acid substitutions (R793M, Q930R, S1096C, S1228T). Because of incomplete penetrance and possible phenocopies pathogenic relevance of the Q930R and S1096C mutations as well as for the previously described A3342G splice site mutation could not be established with certainty. The so far most common mutation (G2019) was not detected in our large cohort. Late onset and typical L-dopa responsive parkinsonian features were generally observed, often accompanied by impairment of executive functions and high interference values in neuropsychological testing, as well as sleeping disturbances but rare hallucinations. There were no abnormalities in electrophysiological investigations. Distinct intrafamily and interfamily differences could be observed, including the clinical presentation of diffuse Lewy body disease in one patient. The frequent finding of cerebral atrophy on MRI and less substantia nigra hyperechogenicity compared with idiopathic Parkinson's disease on transcranial ultrasound needs to be confirmed in further studies. Together with the findings obtained in 46 families in our first study, LRRK2 mutations, therefore, account for 13% of apparently autosomal dominant families in our population with varying but still generally typical clinical presentation of Parkinson's disease.