Cookson Mark R, Xiromerisiou Georgia, Singleton Andrew
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20982-3707, USA.
Curr Opin Neurol. 2005 Dec;18(6):706-11. doi: 10.1097/01.wco.0000186841.43505.e6.
Rapid progress in genetics has meant that there are now five genes identified for 'Parkinson's disease'. The detailed phenotypes vary, but generally the dominant genes cause a Lewy body disease spectrum whereas recessive genes cause a milder parkinsonism with variable inclusion body pathology. The subject of this review is to highlight these discoveries and to discuss their relationships to idiopathic Parkinson's disease.
In January 2004, mutations in PINK1, coding for a mitochondrial kinase, were found to be causal for recessive parkinsonism. Subsequently, several studies have found additional mutations associated with early onset parkinsonism. Some cases have been described with a phenotype much closer to idiopathic Parkinson's disease, but it does not appear that PINK1 is a major risk factor for the sporadic disease. Later in the same year, the LRRK2 gene was shown to cause a dominant disease with a broader phenotype. The protein product was named dardarin and contains GTPase and kinase domains. Lewy bodies have been reported in LRRK2 cases, potentially linking this gene with sporadic Parkinson's disease. One mutation, G2019S, is found in a significant percentage of cases, including sporadic Parkinson's disease.
Mutations in these two genes, along with previously described Mendelian variants, are beginning to yield important information about loss of specific neuronal groups or to protein inclusion pathology. How this relates to sporadic Parkinson's disease, however, is not yet fully defined. There are clear phenotypic overlaps with genetic and sporadic Parkinson's disease, especially for the dominant genes, suggesting that common facets of pathogenesis may exist.
遗传学的快速发展意味着目前已鉴定出五个与“帕金森病”相关的基因。详细的表型各不相同，但一般来说，显性基因会导致路易体病谱系，而隐性基因会导致较轻的帕金森症，并伴有不同的包涵体病理改变。本综述的主题是强调这些发现，并讨论它们与特发性帕金森病的关系。
2004年1月，编码线粒体激酶的PINK1基因突变被发现是隐性帕金森症的病因。随后，多项研究发现了与早发性帕金森症相关的其他突变。一些病例的表型与特发性帕金森病更为接近，但PINK1似乎不是散发性疾病的主要危险因素。同年晚些时候，LRRK2基因被证明会导致一种具有更广泛表型的显性疾病。其蛋白质产物被命名为dardarin，包含GTP酶和激酶结构域。在LRRK2病例中已报告存在路易小体，这可能将该基因与散发性帕金森病联系起来。在相当比例的病例中发现了一种突变，即G2019S，包括散发性帕金森病。
这两个基因的突变，以及先前描述的孟德尔变异，开始产生有关特定神经元群丧失或蛋白质包涵体病理改变的重要信息。然而，这与散发性帕金森病的关系尚未完全明确。遗传型和散发性帕金森病之间存在明显的表型重叠，尤其是对于显性基因，这表明可能存在共同的发病机制。
