RNF213 rare variants in an ethnically diverse population with Moyamoya disease.
RNF213 rare variants in an ethnically diverse population with Moyamoya disease.
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DOI：
10.1161/strokeaha.114.006244
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发表时间：
2014-11
期刊：
影响因子：
8.3
通讯作者：
Milewicz DM
中科院分区：
文献类型：
--
作者：
Cecchi AC;Guo D;Ren Z;Flynn K;Santos-Cortez RL;Leal SM;Wang GT;Regalado ES;Steinberg GK;Shendure J;Bamshad MJ;University of Washington Center for Mendelian Genomics;Grotta JC;Nickerson DA;Pannu H;Milewicz DM
烟雾病（MMD）是一种罕见的，遗传异质性的脑血管疾病造成的闭塞远端颈内动脉。Ring Finger 213基因（RNF 213）的一个变异体，改变了4810位的精氨酸（p.R4810K），与亚洲人群的MMD相关。然而，缺乏关于RNF 213在其他种族和散居亚洲人群的MMD患者中的作用的数据。我们调查了RNF 213变异对美国种族多样性人群MMD的贡献。我们首先对86名不同种族的MMD患者的RNF 213外显子43、44、45（编码epsilon RING指结构域）和外显子60（编码p.R4810K）进行了测序。然后分析来自另外24名MMD患者的综合外显子组测序数据，以在全球范围内识别RNF 213变体。在家族中评估MMD和其他血管疾病的变异分离。RNF 213 p.R4810K在56%（9/16）的亚裔MMD患者中被鉴定，而在94名非亚裔患者中未被鉴定。3.6%（4/110）的患者在编码RING指结构域的外显子中存在变异。在接受外显子组测序的29%（7/24）的MMD患者中鉴定出7种额外的变异。分离分析支持两种变异与MMD相关，一种变异与疾病无关。这些结果证实RNF 213的改变使不同种族的患者易患MMD，并且p.R4810K变体使美国的亚裔个体易患MMD。
Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring Finger 213 gene (RNF213), altering arginine at position 4810 (p.R4810K), is associated with MMD in Asian populations. However, there is a lack of data on the role of RNF213 in MMD patients of additional ethnicities and diasporic Asian populations. We investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States (U.S). We initially sequenced RNF213 exons 43, 44, 45 (encoding the eponymous RING finger domain), and exon 60 (encoding p.R4810K), in 86 ethnically diverse patients with MMD. Comprehensive exome sequencing data from 24 additional MMD patients was then analyzed to globally identify RNF213 variants. Segregation of variants with MMD and other vascular diseases was assessed in families. RNF213 p.R4810K was identified in 56% (9/16) of MMD patients of Asian descent, and not in 94 patients of non-Asian descent. 3.6% (4/110) of patients had variants in the exons encoding the RING finger domain. Seven additional variants were identified in 29% (7/24) of MMD patients who underwent exome sequencing. Segregation analysis supported an association with MMD for two variants, and a lack of association with disease for one variant. These results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the U.S. to MMD.