Identification of RNF213 as a Susceptibility Gene for Moyamoya Disease and Its Possible Role in Vascular Development
Wanyang Liu,Daisuke Morito,Seiji Takashima,Yohei Mineharu,Hatasu Kobayashi,Toshiaki Hitomi,Hirokuni Hashikata,Norio Matsuura,Satoru Yamazaki,Atsushi Toyoda,Ken-ichiro Kikuta,Yasushi Takagi,Kouji H. Harada,Asao Fujiyama,Asao Fujiyama,Roman Herzig,Boris Krischek,Li-Ping Zou,Jeongeun Kim,Masafumi Kitakaze,Susumu Miyamoto,Kazuhiro Nagata,Nobuo Hashimoto,Akio Koizumi +23 more
Reads0
Chats0
TLDR
Evidence is provided suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease, and a founder haplotype transmitted in 42 families is revealed.Abstract:
Background
Moyamoya disease is an idiopathic vascular disorder of intracranial arteries Its susceptibility locus has been mapped to 17q253 in Japanese families, but the susceptibility gene is unknown
Methodology/Principal Findings
Genome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q253 (P<10-4) Fine mapping demonstrated a 15-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 pN321S in PCMTD1 and pR4810K in RNF213 in the 15-Mb locus of the eight index cases The pN321S variant in PCMTD1 could not be confirmed by the Sanger method Sequencing RNF213 in 42 index cases confirmed pR4810K 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 pR4810K A case-control study demonstrated strong association of pR4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 1118 (P = 10−119) Sequencing of RNF213 in East Asian cases revealed additional novel variants: pD4863N, pE4950D, pA5021V, pD5160E, and pE5176G Among Caucasian cases, variants pN3962D, pD4013N, pR4062Q and pP4608S 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 (pR4810K or pD4013N 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
Conclusions/Significance
We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya diseaseread more
Citations
More filters
Book ChapterDOI
Moyamoya Disease (Spontaneous Occlusion of the Circle of Willis)
TL;DR: Moyamoya disease is a chronic progressive stenosis of the terminal portion of the bilateral internal carotid arteries which leads to the formation of an abnormal vascular network composed of collateral pathways at the base of the brain.
Journal ArticleDOI
Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals
Masao Nagasaki,Jun Yasuda,Fumiki Katsuoka,Naoki Nariai,Kaname Kojima,Yosuke Kawai,Yumi Yamaguchi-Kabata,Junji Yokozawa,Inaho Danjoh,Sakae Saito,Yukuto Sato,Takahiro Mimori,Kaoru Tsuda,Rumiko Saito,Xiaoqing Pan,Satoshi Nishikawa,Shin Ito,Yoko Kuroki,Osamu Tanabe,Nobuo Fuse,Shinichi Kuriyama,Hideyasu Kiyomoto,Atsushi Hozawa,Naoko Minegishi,James Douglas Engel,Kengo Kinoshita,Shigeo Kure,Nobuo Yaegashi,Masayuki Yamamoto +28 more
TL;DR: The value of high-coverage sequencing for constructing population-specific variant panels, which covers 99.0% SNVs of minor allele frequency ≥0.1%, is demonstrated, and its value for identifying causal rare variants of complex human disease phenotypes in genetic association studies is demonstrated.
Journal ArticleDOI
Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease.
Satoko Miyatake,Noriko Miyake,H. Touho,Akira Nishimura-Tadaki,Yukiko Kondo,Ippei Okada,Yoshinori Tsurusaki,Hiroshi Doi,Haruya Sakai,Hirotomo Saitsu,Keiko Shimojima,Toshiyuki Yamamoto,M. Higurashi,N. Kawahara,H. Kawauchi,Kazunori Nagasaka,Nobuhiko Okamoto,T. Mori,Shigeru Koyano,Yoshiyuki Kuroiwa,Masataka Taguri,Satoshi Morita,Yoichi Matsubara,Shigeo Kure,Naomichi Matsumoto +24 more
TL;DR: The homozygous c.14576G>A variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy.
Journal ArticleDOI
Intracranial Atherosclerosis: Current Understanding and Perspectives
TL;DR: Recently large clinical trials of ICAD, which evaluated the effectiveness of anticoagulation and stenting to prevent thromboembolism and restore hemodynamic compromise, failed to reduce major vascular events in patients with ICAD.
References
More filters
Journal ArticleDOI
Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold.
TL;DR: Related sequences in both alpha and beta and in other enzymes that bind ATP or ADP in catalysis help to identify regions contributing to an adenine nucleotide binding fold in both ATP synthase subunits.
Journal Article
Parametric and nonparametric linkage analysis: a unified multipoint approach.
TL;DR: It is shown that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis, and appears to be the method of choice for pedigree studies of complex traits.
Journal ArticleDOI
Cerebrovascular "moyamoya" disease. Disease showing abnormal net-like vessels in base of brain.
Jiro Suzuki,Akira Takaku +1 more
TL;DR: The disease which produces an abnormal net-like blood vessel picture in the base of the brain might have been observed in this country during these 10 years, but visualization of such an angiogram seems not to have been noticed as indicating a disease with characteristic features.
Journal ArticleDOI
In vivo imaging of embryonic vascular development using transgenic zebrafish.
TL;DR: It is found that the zebrafish fli1 promoter is able to drive expression of enhanced green fluorescent protein (EGFP) in all blood vessels throughout embryogenesis, and these transgenic lines allow detailed analysis of both wild type and mutant embryonic vasculature.
Journal ArticleDOI
Targeted capture and massively parallel sequencing of 12 human exomes
Sarah B H Ng,Emily H. Turner,Peggy D. Robertson,Steven D. Flygare,Abigail W. Bigham,Choli Lee,Tristan Shaffer,Michelle Wong,Arindam Bhattacharjee,Evan E. Eichler,Michael J. Bamshad,Deborah A. Nickerson,Jay Shendure +12 more
TL;DR: It is shown that candidate genes for Mendelian disorders can be identified by exome sequencing of a small number of unrelated, affected individuals, and may be extendable to diseases with more complex genetics through larger sample sizes and appropriate weighting of non-synonymous variants by predicted functional impact.
Related Papers (5)
A genome-wide association study identifies RNF213 as the first Moyamoya disease gene
Cerebrovascular "moyamoya" disease. Disease showing abnormal net-like vessels in base of brain.
Jiro Suzuki,Akira Takaku +1 more
Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease.
Satoko Miyatake,Noriko Miyake,H. Touho,Akira Nishimura-Tadaki,Yukiko Kondo,Ippei Okada,Yoshinori Tsurusaki,Hiroshi Doi,Haruya Sakai,Hirotomo Saitsu,Keiko Shimojima,Toshiyuki Yamamoto,M. Higurashi,N. Kawahara,H. Kawauchi,Kazunori Nagasaka,Nobuhiko Okamoto,T. Mori,Shigeru Koyano,Yoshiyuki Kuroiwa,Masataka Taguri,Satoshi Morita,Yoichi Matsubara,Shigeo Kure,Naomichi Matsumoto +24 more