A new gene for Parkinson's disease: should we care?
A new gene for Parkinson's disease: should we care?
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帕金森病的新基因：我们应该关心吗？
DOI：
10.1016/s1474-4422(14)70270-4
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Singleton,Andrew
中科院分区：
文献类型：
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作者：
Singleton,Andrew
在过去的二十年里，帕金森病的几个遗传原因和风险因素已经出现。在《柳叶刀神经病学》中，Manabu Funayama及其同事描述了一系列实验，他们认为CHCHD2突变是帕金森病的一种新原因。他们研究了一个多代同堂的大家庭，该家庭患有明显的常染色体显性形式的帕金森病。通过使用连锁以及全外显子组和全基因组测序的组合，他们提名CHCHD2中的突变（Thr61Ile）为疾病的原因。在这一初步发现之后，Funayama及其同事随后筛选了一系列家族性（n= 341）或散发性（n= 517）帕金森病患者，以及一系列对照（n= 559）。他们确定了另外三个CHCHD2突变的家庭：一个具有相同Thr61Ile突变的家庭，一个具有Arg145Gln突变的家庭，以及一个具有剪接位点突变（300+ 5G> A）的家庭。这两个具有相同突变的家族似乎无关，并且最初的遗传学证据表明该突变在每个家族中独立出现。从遗传学的角度来看，这些发现具有相当的说服力，尽管独立鉴定具有CHCHD2突变的其他家族应被视为证明致病性的必要条件。与这些突变相关的临床表型似乎与典型的帕金森病相似，发病年龄在50多岁，左旋多巴反应性帕金森综合征。
Over the past two decades, several genetic causes of and risk factors for Parkinson's disease have emerged. In The Lancet Neurology, Manabu Funayama and colleagues 1 describe a series of experiments that they argue nominate CHCHD2 mutations as a novel cause of Parkinson's disease. They studied a large multigenerational family with an apparent autosomal dominant form of Parkinson's disease. Through the use of linkage and a combination of whole-exome and whole-genome sequencing, they nominated a mutation (Thr61Ile) within CHCHD2 as the cause of disease. After this initial finding, Funayama and colleagues then screened a large series of patients with familial (n= 341) or sporadic (n= 517) Parkinson's disease, and a series of controls (n= 559). They identified three additional families with CHCHD2 mutations: a family with the same Thr61Ile mutation, a family with an Arg145Gln mutation, and a family with a splice-site mutation (300+ 5G> A). The two families with the same mutation seem to be unrelated, and the initial genetic evidence suggests that this mutation arose independently in each family.From a genetic perspective, these findings are fairly persuasive, although independent identification of additional families with CHCHD2 mutations should be regarded as a requirement for proving pathogenicity. The clinical phenotype associated with these mutations seems to be similar to typical Parkinson's disease, with an age at onset in the 50s and levodopa-responsive parkinsonism.