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Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development.

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 - PLoS ONE (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Health and Environmental Sciences, Kyoto University, Kyoto, Japan.

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.

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.

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Related in: MedlinePlus

Transmission patterns of the haplotypes in 42 families.The numbers in the parentheses indicate the haplotypes transmitted in each family. Haplotype 1 symbolizes non-risk haplotypes collectively. Therefore it comprises various haplotypes. Haplotypes can be seen in Figure 5. Several family members that were genotyped were omitted in the pedigree chart for clarity. Those members and their haplotypes were; two siblings (1,1) for pedigree 7; father (1,1) for pedigree 21; father (1,1) for pedigree 22; father (1, 1) and a sibling (1,1) for pedigree 23; father (1,1), mother (2,1) and a sibling (1,1) for pedigree 26; three siblings (1,1), (1,1) and (1,1) for pedigree 27; father (1,1), three siblings (1,1) (1,1) and (1,1) for pedigree 28; father (1,1), mother (2,1) and a child of 2 (1,1) for pedigree 32; three siblings (1,1), (1,1), and (1,1) for pedigree 33; mother (1,1) for pedigree 34; father (1,1) and mother (2,1) for pedigree 36; a sibling (1,1) for pedigree 39; three siblings (1,1), (4,1) and (1,1) for pedigree 40; father (2,1) for pedigree 41; mother (1,1) for pedigree 42.
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pone-0022542-g004: Transmission patterns of the haplotypes in 42 families.The numbers in the parentheses indicate the haplotypes transmitted in each family. Haplotype 1 symbolizes non-risk haplotypes collectively. Therefore it comprises various haplotypes. Haplotypes can be seen in Figure 5. Several family members that were genotyped were omitted in the pedigree chart for clarity. Those members and their haplotypes were; two siblings (1,1) for pedigree 7; father (1,1) for pedigree 21; father (1,1) for pedigree 22; father (1, 1) and a sibling (1,1) for pedigree 23; father (1,1), mother (2,1) and a sibling (1,1) for pedigree 26; three siblings (1,1), (1,1) and (1,1) for pedigree 27; father (1,1), three siblings (1,1) (1,1) and (1,1) for pedigree 28; father (1,1), mother (2,1) and a child of 2 (1,1) for pedigree 32; three siblings (1,1), (1,1), and (1,1) for pedigree 33; mother (1,1) for pedigree 34; father (1,1) and mother (2,1) for pedigree 36; a sibling (1,1) for pedigree 39; three siblings (1,1), (4,1) and (1,1) for pedigree 40; father (2,1) for pedigree 41; mother (1,1) for pedigree 42.

Mentions: We determined the minor allele frequencies for five unregistered variants found in this study and a previous study [21] in Japanese controls. The frequencies were 0.012 (p1 = 9/768) for ss179362671, 0.014 (p2 = 11/768) for ss179362673, 0.013 (p3 = 10/768) for ss179362674, 0.022 (p4 = 17/768) for ss179362675 and 0.010 (p5 = 8/768) for ss161110142 in 384 Japanese controls, indicating that they are all rare variants. We then genotyped the 42 families. As shown in Figure 4, these four rare variants were transmitted en bloc with p.R4810K. They comprised five subhaplotypes (Figure 5); and p.R4810K was not transmitted alone in any of the families.


Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development.

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 - PLoS ONE (2011)

Transmission patterns of the haplotypes in 42 families.The numbers in the parentheses indicate the haplotypes transmitted in each family. Haplotype 1 symbolizes non-risk haplotypes collectively. Therefore it comprises various haplotypes. Haplotypes can be seen in Figure 5. Several family members that were genotyped were omitted in the pedigree chart for clarity. Those members and their haplotypes were; two siblings (1,1) for pedigree 7; father (1,1) for pedigree 21; father (1,1) for pedigree 22; father (1, 1) and a sibling (1,1) for pedigree 23; father (1,1), mother (2,1) and a sibling (1,1) for pedigree 26; three siblings (1,1), (1,1) and (1,1) for pedigree 27; father (1,1), three siblings (1,1) (1,1) and (1,1) for pedigree 28; father (1,1), mother (2,1) and a child of 2 (1,1) for pedigree 32; three siblings (1,1), (1,1), and (1,1) for pedigree 33; mother (1,1) for pedigree 34; father (1,1) and mother (2,1) for pedigree 36; a sibling (1,1) for pedigree 39; three siblings (1,1), (4,1) and (1,1) for pedigree 40; father (2,1) for pedigree 41; mother (1,1) for pedigree 42.
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pone-0022542-g004: Transmission patterns of the haplotypes in 42 families.The numbers in the parentheses indicate the haplotypes transmitted in each family. Haplotype 1 symbolizes non-risk haplotypes collectively. Therefore it comprises various haplotypes. Haplotypes can be seen in Figure 5. Several family members that were genotyped were omitted in the pedigree chart for clarity. Those members and their haplotypes were; two siblings (1,1) for pedigree 7; father (1,1) for pedigree 21; father (1,1) for pedigree 22; father (1, 1) and a sibling (1,1) for pedigree 23; father (1,1), mother (2,1) and a sibling (1,1) for pedigree 26; three siblings (1,1), (1,1) and (1,1) for pedigree 27; father (1,1), three siblings (1,1) (1,1) and (1,1) for pedigree 28; father (1,1), mother (2,1) and a child of 2 (1,1) for pedigree 32; three siblings (1,1), (1,1), and (1,1) for pedigree 33; mother (1,1) for pedigree 34; father (1,1) and mother (2,1) for pedigree 36; a sibling (1,1) for pedigree 39; three siblings (1,1), (4,1) and (1,1) for pedigree 40; father (2,1) for pedigree 41; mother (1,1) for pedigree 42.
Mentions: We determined the minor allele frequencies for five unregistered variants found in this study and a previous study [21] in Japanese controls. The frequencies were 0.012 (p1 = 9/768) for ss179362671, 0.014 (p2 = 11/768) for ss179362673, 0.013 (p3 = 10/768) for ss179362674, 0.022 (p4 = 17/768) for ss179362675 and 0.010 (p5 = 8/768) for ss161110142 in 384 Japanese controls, indicating that they are all rare variants. We then genotyped the 42 families. As shown in Figure 4, these four rare variants were transmitted en bloc with p.R4810K. They comprised five subhaplotypes (Figure 5); and p.R4810K was not transmitted alone in any of the families.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Health and Environmental Sciences, Kyoto University, Kyoto, Japan.

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.

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.

Show MeSH
Related in: MedlinePlus