RNF213 as the major susceptibility gene for Chinese patients with moyamoya disease and its clinical relevance
RNF213 as the major susceptibility gene for Chinese patients with moyamoya disease and its clinical relevance
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DOI：
10.3171/2016.2.jns152173
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发表时间：
2017-04-01
影响因子：
4.1
通讯作者：
Zhao, Jizong
中科院分区：
文献类型：
--
作者：
Zhang, Qian;Liu, Yaping;Zhao, Jizong
目的 烟雾病（MMD）是一种罕见的遗传异质性脑血管疾病。作者对非常有趣的新基因（RING）指蛋白213（RNF213）进行了遗传学研究；肌动蛋白α2 (ACTA2);含有 BRCA1/BRCA2 的复合亚基 3 (BRCC3)；和鸟苷酸环化酶 1，可溶性，α 3 (GUCY1A3) 以及中国 MMD 患者的临床表型分析，以确定遗传差异是否是不同种族 MMD 中出现的不同临床特征的原因。 方法 设计小组来识别 MMD 基因的致病突变以及涉及相关疾病的突变（RNF213、ACTA2、BRCC3 和 GUCY1A3）。该小组用于检测 255 名中国 MMD 患者的致病突变。比较了患者和 300 名对照者的基因型和等位基因频率。对 34 个家系进行了突变分离分析，并建立了基因型-表型相关性。结果 鉴定出 27 个 RNF213 罕见错义变异，在对照中未发现。其中，31.4% 的 MMD 患者（255 名患者中的 80 名）检测到 p.R4810K。与对照组相比，MMD 患者的 A 等位基因和 p.R4810K G/A 基因型的频率显着升高（chi(2) = 104.166，p < 0.000）。在 10.6% 的无 p.R4810K 变异的患者（255 名患者中的 27 名）中发现了 25 种罕见变异。分离分析支持 MMD 和 3 个变体之间的关联。 ACTA2、BRCC3 或 GUCY1A3 中未发现可能的致病突变。与 RNF213 中没有罕见变异的患者相比，p.R4810K 杂合子患者诊断时更年轻（25 岁 vs 29 岁，p = 0.049），并且有更多的家族病例（24% vs 4.4%，p = 0.000）、缺血病例（81.3% vs 67.5%，p = 0.037）和大脑后动脉受累。 (52% vs 32.5%, p = 0.007)。 结论 RNF213是中国MMD患者的主要易感基因。在中国 MMD 患者中发现的罕见变异谱是多种多样的。与RNF213中没有罕见变异的患者相比，p.R4810K杂合子患者表现出不同的临床特征。
OBJECTIVE Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease. The authors conducted a genetic study of really interesting new gene (RING) finger protein 213 (RNF213); actin alpha 2 (ACTA2); BRCA1/BRCA2-containing complex subunit 3 (BRCC3); and guanylate cyclase 1, soluble, alpha 3 (GUCY1A3) as well as a clinical phenotype analysis in Chinese MMD patients to determine whether genetic differences are responsible for the different clinical features that appear in MMD in different ethnicities.METHODS A panel was designed to identify disease-causing mutations in MMD genes and those involved in related disorders (RNF213, ACTA2, BRCC3, and GUCY1A3). The panel was used to detect disease-causing mutations in 255 Chinese MMD patients. Genotype and allele frequencies were compared between patients and 300 controls. A mutation segregation analysis was performed in 34 families, and genotype-phenotype correlations were made.RESULTS Twenty-seven rare missense variants of RNF213 were identified and were not found in controls. Among them, p.R4810K was identified in 31.4% of patients (80 of 255) with MMD. Significantly higher frequencies of the A allele and G/A genotype of p.R4810K were observed in MMD patients compared with controls (chi(2) = 104.166, p < 0.000). Twenty-five rare variants were identified in 10.6% of patients (27 of 255) without p.R4810K variants. Segregation analysis supported an association between MMD and 3 variants. No possible disease-causing mutations were identified in ACTA2, BRCC3, or GUCY1A3. Compared with patients without the rare variants in RNF213, the p.R4810K heterozygous patients were younger at diagnosis (25 vs 29 years old, p = 0.049) and had more familial cases (24% vs 4.4%, p = 0.000), ischemic cases (81.3% vs 67.5%, p = 0.037), and involvement of the posterior cerebral artery (52% vs 32.5%, p = 0.007).CONCLUSIONS RNF213 is the major susceptibility gene in Chinese MMD patients. The spectrum of rare variants identified in Chinese MMD patients was diverse. Compared to patients without the rare variants in RNF213, the p.R4810K heterozygous patients exhibited different clinical features.