The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease.
The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease.
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DOI：
10.1186/s13024-015-0045-4
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发表时间：
2015-09-24
影响因子：
15.1
通讯作者：
Zabetian CP
中科院分区：
文献类型：
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作者：
Mata IF;Jang Y;Kim CH;Hanna DS;Dorschner MO;Samii A;Agarwal P;Roberts JW;Klepitskaya O;Shprecher DR;Chung KA;Factor SA;Espay AJ;Revilla FJ;Higgins DS;Litvan I;Leverenz JB;Yearout D;Inca-Martinez M;Martinez E;Thompson TR;Cholerton BA;Hu SC;Edwards KL;Kim KS;Zabetian CP
确定美国帕金森病（PD）多发病家族的致病基因。我们描述了一个具有经典PD表型的家族，其中7名个体（5名男性和2名女性）受到影响，平均发病年龄为46.1岁（范围，29-57岁）。我们对4名患病和1名未患病的家庭成员进行了全外显子组测序。然后使用Sanger测序来验证和分型谱系的其余部分中的所有候选变体。用野生型或突变体构建体转染的培养细胞用于表征感兴趣的蛋白质。我们在RAB 39 B基因中发现了一个错义突变（c.574G > A; p.G192R），该突变与疾病密切相关，并表现出X连锁显性遗传，女性中的遗传率降低。该突变发生在高度保守的氨基酸残基中，并且在外显子组聚集联盟数据集中的87，725个X染色体中未观察到。对587例家族性PD病例中的RAB 39 B编码区进行测序，产生了两个额外的突变（c.428 C> G [p.A143 G]和c.624_626 delGAG [p.R209 del]），这些突变在计算机模拟中被预测为有害的，但发生在信息不足以评估疾病分离的家族中。在PC 12和SK-N-BE（2）C细胞中的实验表明，p.G192R可能通过改变介导细胞内靶向的高变C末端结构域的结构而导致突变蛋白的错误定位。我们的研究结果涉及RAB 39 B，囊泡运输的重要调节剂，在临床上典型的PD。进一步表征正常和异常的RAB 39 B功能可能阐明PD和相关疾病中神经变性的重要机制。本文的在线版本（doi：10.1186/s13024-015-0045-4）包含补充材料，可供授权用户使用。
To identify the causal gene in a multi-incident U.S. kindred with Parkinson’s disease (PD). We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders. The online version of this article (doi:10.1186/s13024-015-0045-4) contains supplementary material, which is available to authorized users.