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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.    Methodology/Principal Findings  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/Significance  We provide evidence suggesting, for the first time, the involvement of  RNF213  in genetic susceptibility to moyamoya disease.

Identification of RNF213 as a Susceptibility Gene for Moyamoya Disease and Its Possible Role in Vascular Development