A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease
A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease
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DOI：
10.1016/j.ajhg.2011.06.008
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发表时间：
2011-07-15
影响因子：
9.8
通讯作者：
Strom, Tim M.
中科院分区：
文献类型：
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作者：
Zimprich, Alexander;Benet-Pages, Anna;Strom, Tim M.
为了确定晚发性帕金森病（PD）的罕见致病变异，我们通过外显子组测序调查了一个奥地利家庭，其中有16名受影响的个体。我们发现了一个错义突变，c.1858G>A（p.Asp620Asn），在VPS 35基因在所有7个受影响的家庭成员谁是活着的。通过筛选额外的PI）病例，我们发现在另外两个分别有5名和10名受影响成员的家族中，相同的变异以常染色体显性模式与疾病共分离，具有高但不完全的遗传率。受影响个体的平均发病年龄为53岁。基因分型表明，共享的单倍型延伸到VPS 35周围的65个酶。在另外860例病例和1014例对照中筛选整个VPS 35编码序列，发现了另外6种非同义错义变体。三种仅存在于病例中，两种仅存在于对照中，一种存在于病例和对照中。家族性突变p.Asp620Asn和进一步的变异，c.1570C>T（p.Arg524Trp），在散发性PD病例中检测到的预测是破坏性的基于序列和分子动力学分析。VPS 35是retromer复合物的一个组分，介导内体和trans-Golgi网络之间的逆行转运，最近发现它与阿尔茨海默病有关。
To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PI) cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.