A genome-wide association study identifies RNF213 as the first Moyamoya disease gene
A genome-wide association study identifies RNF213 as the first Moyamoya disease gene
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DOI：
10.1038/jhg.2010.132
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发表时间：
2011-01-01
影响因子：
3.5
通讯作者：
Kure, Shigeo
中科院分区：
文献类型：
--
作者：
Kamada, Fumiaki;Aoki, Yoko;Kure, Shigeo
烟雾病（MMD）是一种以双侧颈内动脉狭窄和异常侧支血管为特征的进行性脑血管病。虽然类似于15%的MMD病例是家族性的，但MMD基因仍然未知。对785 720个单核苷酸多态性（SNPs）进行了全基因组关联研究，比较了72名日本MMD患者和45名日本对照，结果发现染色体17 q25-ter与MMD风险有很强的关联。这一结果进一步证实了基因座特异性关联研究使用335个SNPs在17 q25-ter区域。在RNF 213位点上由7个SNPs组成的单倍型与MMD密切相关（P = 5.3 × 10 - 10）。RNF 213编码一种非常有趣的新基因指蛋白，具有AAA ATP酶结构域，并在脾脏和白细胞中大量表达。小鼠组织的RNA原位杂交分析表明，成熟的淋巴细胞表达更高水平的Rnf 213 mRNA比其未成熟的同行。RNF 213的突变分析显示，在95%的MMD家族、73%的非家族性MMD病例和1.4%的对照中存在创始者突变p.R4859K;该突变大大增加了MMD的风险（P = 1.2 x 10（-43），比值比-190.8，95%置信区间-71.7-507.9）。在p.R4859K阴性患者中鉴定出另外三种错义突变。这些结果表明，RNF 213是第一个确定的MMD易感基因。Journal of Human Genetics（2011）56，34-40; doi：10.1038/jhg.2010.132; 2010年11月4日在线发表
Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. Although similar to 15% of MMD cases are familial, the MMD gene(s) remain unknown. A genome-wide association study of 785 720 single-nucleotide polymorphisms (SNPs) was performed, comparing 72 Japanese MMD patients with 45 Japanese controls and resulting in a strong association of chromosome 17q25-ter with MMD risk. This result was further confirmed by a locus-specific association study using 335 SNPs in the 17q25-ter region. A single haplotype consisting of seven SNPs at the RNF213 locus was tightly associated with MMD (P = 5.3 x 10(-10)). RNF213 encodes a really interesting new gene finger protein with an AAA ATPase domain and is abundantly expressed in spleen and leukocytes. An RNA in situ hybridization analysis of mouse tissues indicated that mature lymphocytes express higher levels of Rnf213 mRNA than their immature counterparts. Mutational analysis of RNF213 revealed a founder mutation, p.R4859K, in 95% of MMD families, 73% of non-familial MMD cases and 1.4% of controls; this mutation greatly increases the risk of MMD (P = 1.2 x 10(-43), odds ratio-190.8, 95% confidence interval-71.7-507.9). Three additional missense mutations were identified in the p.R4859K-negative patients. These results indicate that RNF213 is the first identified susceptibility gene for MMD. Journal of Human Genetics (2011) 56, 34-40; doi:10.1038/jhg.2010.132; published online 4 November 2010