title: Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease.
authors.affiliation: Department of Health and Environmental Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Wanyang
authors.initials: W
authors.lastname: Liu
authors.forename: Daisuke
authors.initials: D
authors.lastname: Morito
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mineharu
authors.forename: Hatasu
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hitomi
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Hashikata
authors.forename: Norio
authors.initials: N
authors.lastname: Matsuura
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Toyoda
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Kikuta
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takagi
authors.forename: Kouji H
authors.initials: KH
authors.lastname: Harada
authors.forename: Asao
authors.initials: A
authors.lastname: Fujiyama
authors.forename: Roman
authors.initials: R
authors.lastname: Herzig
authors.forename: Boris
authors.initials: B
authors.lastname: Krischek
authors.forename: Liping
authors.initials: L
authors.lastname: Zou
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Susumu
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagata
authors.forename: Nobuo
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000251:Adenosine Triphosphatases; D000328:Adult; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001808:Blood Vessels / Q000378:metabolism / Q000503:physiopathology*; D016022:Case-Control Studies; D003001:Cloning, Molecular; D056915:DNA Copy Number Variations / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009072:Moyamoya Disease / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology*; D016366:Open Reading Frames / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish
chemical_list: D020413:3' Untranslated Regions; D018076:DNA, Complementary; C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases