Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development.
Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development.
复制标题
DOI：
10.1371/journal.pone.0022542
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Koizumi A
中科院分区：
文献类型：
--
作者：
Liu W;Morito D;Takashima S;Mineharu Y;Kobayashi H;Hitomi T;Hashikata H;Matsuura N;Yamazaki S;Toyoda A;Kikuta K;Takagi Y;Harada KH;Fujiyama A;Herzig R;Krischek B;Zou L;Kim JE;Kitakaze M;Miyamoto S;Nagata K;Hashimoto N;Koizumi A
烟雾病是一种特发性颅内动脉血管疾病。在日本家庭中，其易感基因已定位于17q25.3，但易感基因尚不清楚。对8个三代烟雾病家系进行全基因组连锁分析，发现与17q25.3连锁（P<10-4）。精细定位显示了由D17 S1806和rs 2280147限定的1.5 Mb疾病位点。我们对这些家族中的8个指标病例进行了外显子组分析，结果通过Ng标准过滤。在8例索引病例的1.5-Mb位点中，PCMTD 1的p.N321S和RNF 213的p.R4810K存在变异。桑格法不能确认PCMTD 1中的p.N321 S变异体。对42例指示病例中的RNF 213进行测序证实了p.R4810K，并发现它是唯一未注册的变体。对RNF 213基因的39个SNPs进行基因分型，发现一个创始人单倍型在42个家系中传播。测序260 kb的区域覆盖的创始人单倍型在一个索引的情况下，没有显示任何编码变异，除了p.R4810K。一项病例对照研究表明，东亚人群（251例病例和707例对照）中p.R4810K与烟雾病密切相关，比值比为111.8（P = 10−119）。 在东亚病例中，RNF 213的测序发现了其他新的变体：p.D4863N、p.E4950D、p.A5021V、p.D5160E和p.E5176G。在高加索病例中，鉴定出了变体p.N3962D、p.D4013N、p.R4062Q和p.P4608S。RNF 213编码591-kDa的胞质蛋白，其具有两个功能结构域：步行者基序和RING指结构域。它们表现出ATP酶和泛素连接酶活性。虽然突变等位基因（P.R4810K或P.D4013N在RING结构域）不影响转录水平或泛素化活性，敲低RNF 213在斑马鱼引起不规则的壁形成的主干动脉和异常发芽血管。我们首次提供证据表明RNF 213参与烟雾病的遗传易感性。
Moyamoya disease is an idiopathic vascular disorder of intracranial arteries. Its susceptibility locus has been mapped to 17q25.3 in Japanese families, but the susceptibility gene is unknown. Genome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q25.3 (P<10-4). Fine mapping demonstrated a 1.5-Mb disease locus bounded by D17S1806 and rs2280147. We conducted exome analysis of the eight index cases in these families, with results filtered through Ng criteria. There was a variant of p.N321S in PCMTD1 and p.R4810K in RNF213 in the 1.5-Mb locus of the eight index cases. The p.N321S variant in PCMTD1 could not be confirmed by the Sanger method. Sequencing RNF213 in 42 index cases confirmed p.R4810K and revealed it to be the only unregistered variant. Genotyping 39 SNPs around RNF213 revealed a founder haplotype transmitted in 42 families. Sequencing the 260-kb region covering the founder haplotype in one index case did not show any coding variants except p.R4810K. A case-control study demonstrated strong association of p.R4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 111.8 (P = 10−119). Sequencing of RNF213 in East Asian cases revealed additional novel variants: p.D4863N, p.E4950D, p.A5021V, p.D5160E, and p.E5176G. Among Caucasian cases, variants p.N3962D, p.D4013N, p.R4062Q and p.P4608S were identified. RNF213 encodes a 591-kDa cytosolic protein that possesses two functional domains: a Walker motif and a RING finger domain. These exhibit ATPase and ubiquitin ligase activities. Although the mutant alleles (p.R4810K or p.D4013N in the RING domain) did not affect transcription levels or ubiquitination activity, knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels. We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease.
登录
查看更多内容
影响因子：
--
作者：
Alvarez Y;Cederlund ML;Cottell DC;Bill BR;Ekker SC;Torres-Vazquez J;Weinstein BM;Hyde DR;Vihtelic TS;Kennedy BN
通讯作者：
Kennedy BN
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8.3
作者：
Kim, SK;Yoo, JI;Wang, KC
通讯作者：
Wang, KC
影响因子：
2.6
作者：
El Ramahi, KM;Al Rayes, HM
通讯作者：
Al Rayes, HM
影响因子：
1.9
作者：
Goto, Yasunobu;Yonekawa, Yasuhiro
通讯作者：
Yonekawa, Yasuhiro