Parkinson's genetics: an embarrassment of riches.
Parkinson's genetics: an embarrassment of riches.
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帕金森氏症遗传学：财富的尴尬。
DOI：
10.1002/ana.10091
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发表时间：
2002
影响因子：
11.2
通讯作者：
Farrer,Matt
中科院分区：
文献类型：
--
作者：
Gwinn-Hardy,Katrina;Farrer,Matt
经过深入的流行病学研究，帕金森病（PD）被认为是典型的“非遗传性疾病”。尽管有这样的背景，但有两个基因与疾病明确相关：α-突触核蛋白1 （PARK1）和parkin2 （PARK2）。越来越多的证据表明第三种泛素c端水解酶e3, 4 (PARK5)，并且有5种遗传连锁（PARK3, 4, 6, 7和8）与其他正在进行的基因连锁。最近的遗传研究表明，遗传在人群中的“典型”帕金森病中起作用，而位置克隆研究所涉及的基因和遗传变异被证明是散发性疾病的危险因素。Valente及其同事13 （Annals of Neurology，本期）现在为染色体1p35-p36 （D1S483-9cM-D1S2674）上的PARK6提供了额外的支持，这是最近在1号染色体短臂上报道的帕金森病的三个位点（PARK6、7和8）之一。这一发现进一步强调了遗传学在帕金森病中的重要性；作者证明，PARK6位点与欧洲相当多的隐性遗传PD病例有关（28个家庭中有8个家庭的parkin基因PARK2突变均为阴性）。在Valente和同事对PARK6 （MIM 605909）的初步报告之后，van Duijn和同事对PARK7的研究紧随其后。8 PARK6 （D1S483-9cM-D1S2674）在意大利的一个近亲家族（Marsala家族）中被鉴定为着丝性更强；PARK7 （D1S243-16cM-D1S244）位于p臂端粒附近，通过全基因组连锁分析在荷兰西南部的一个近亲家族中发现。PARK6和PARK7位点在遗传和临床上是不同的。来自Masala家族（PARK6）的患者在32 - 48岁时表现不对称，以休息性震颤为主，轻度至中度帕金森病。该疾病进展缓慢，对左旋多巴反应良好，尽管左旋多巴引起的运动障碍的严重程度不同。目前记录的16例患者中，没有一例肌张力障碍或睡眠益处被注意到，这将这些患者与帕金森病（PARK2）患者区分开来。在park7相关个体中，帕金森病出现在38至50岁；同样，症状主要是不对称的，进展缓慢，对左旋多巴治疗反应良好。值得注意的是，4例患者中有3例无静息性震颤，3例在病程早期有行为/精神障碍，2例出现局灶性肌张力障碍（眼睑痉挛）。PARK6和PARK7均未见病理记录，PARK7的归属仍需通过鉴定其他相关家族来确认。PARK7与DYT13重叠，DYT13是原发性扭转肌张力障碍的主要基因位点。虽然这些运动障碍的遗传模式和表现不同，但PARK7和DYT13是等位基因疾病并非不可思议。在某种程度上，冰岛最近的一项研究表明，普遍存在的遗传变异是岛上帕金森氏症的一个主要原因，这在一定程度上取代了对几个隐性基因座PARK2、6和7的发现。冰岛的轨迹即将被报道。据估计，在欧洲具有隐性遗传的早发性帕金森病患者中，帕金森基因突变（PARK2）的发生率为49%，而在45岁的散发性帕金森病患者中，PARK2的发生率为18%。PARK6突变可能导致相似数量的患者。总的来说，这些发现支持这样一种观点，即帕金森病一般可能是由遗传和随机因素混合引起的。
After intensive epidemiological study, Parkinson’s disease (PD) had been considered the archetypal “nongenetic disorder. Despite this background, two genes are clearly associated with disease: α-synuclein1 (PARK1) and parkin2 (PARK2). There is increasing evidence implicating a third, ubiquitin C-terminal hydrolase3, 4 (PARK5), and there are five genetic linkages (PARK3, 4, 6, 7, and 8) with others in the pipeline. 5–9 Recent heritability studies suggest that genetics plays a role in “typical” Parkinson’s disease in the population, 10 whereas genes and genetic variability implicated by positional cloning studies are demonstrated to be risk factors for the sporadic condition. 1, 11, 12 Valente and colleagues13 (Annals of Neurology, this issue) now provide additional support for PARK6 on chromosome 1p35–p36 (D1S483-9cM-D1S2674), one of three loci (PARK6, 7, and 8) for parkinsonism that was recently reported on the short arm of chromosome 1. This finding further highlights the importance of genetics in parkinsonism; the authors demonstrate that the PARK6 locus contributes to recessively inherited PD in a relatively large number of cases in Europe (8 of 28 families examined, all negative for mutations in the parkin gene, PARK2). The initial report by Valente and colleagues7 of PARK6 (MIM 605909) was closely followed by the assignment of PARK7 by van Duijn and colleagues. 8 PARK6 (D1S483-9cM-D1S2674), which is more centromeric, was identified in a consanguineous family from Italy (the Marsala kindred); PARK7 (D1S243-16cM-D1S244), which is closer to the “p-arm” telomere, was found through genomewide linkage analysis in a consanguineous family from the southwest Netherlands. PARK6 and PARK7 loci are genetically and clinically distinct. Patients from the Masala kindred (PARK6) presented asymmetrically at 32 to 48 years of age, with rest tremor predominant, mild to moderate parkinsonism. The disease has a slow progression, with good response to L-Dopa, albeit with L-Dopa-induced dyskinesias of variable severity. In none of 16 patients, now documented, are dystonia or sleep benefit noted, distinguishing these patients from those with parkin-proven (PARK2) disease. In PARK7-linked individuals, parkinsonism presented at 38 to 50 years at age; again, symptoms were primarily asymmetric with slow progression and good response to L-Dopa therapy. Notably, resting tremor was absent in 3 of 4 patients, 3 had behavioral/psychic disturbances early in the disease course, and 2 patients suffered focal dystonia (blepharospasm). In neither PARK6 nor PARK7 has pathology been documented, and the PARK7 assignment remains to be confirmed by identification of other linked families. PARK7 overlaps with DYT13, a dominant locus for primary torsion dystonia. 13 Although the mode of inheritance and presentations of these movement disorders is different, it is not inconceivable that PARK7 and DYT13 are allelic disorders. The discovery of several recessive loci, PARK2, 6, and 7, that contribute to disease was preempted, in part, by a recent Icelandic study suggesting that prevalent genetic variability is a major contributor to Parkinson’s disease on the island9; the Icelandic locus is about to be reported. 9 The frequency of parkin mutations (PARK2) in Europe has been estimated at 49% in families with early-onset parkinsonism compatible with recessive inheritance, and in 18% of patients with sporadic parkinsonism with onset 45 years. 15 PARK6 mutations may account for a similar number of patients. In total these findings support the notion that Parkinson’s disease in general, may be caused by a mixture of genetic and stochastic …