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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

Clinical features of moyamoya disease.(A) An anterior-posterior and lateral views of left internal carotid angiography in a 9-year-old child with moyamoya disease (right) and an 8-year-old control child (left). An occlusion with moyamoya vessels can be seen around the terminal portion of the internal carotid artery and proximal portions of the anterior cerebral artery and middle cerebral artery in the affected child. (B) Intimal hyperplasia in the middle cerebral artery from an autopsy of a 69-year-old case. Intimal hyperplasia (red arrowhead), atrophic media (red arrow) and winding internal elastic lamina (black arrow) can be seen with Elastica Masson staining, ×200.
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pone-0022542-g001: Clinical features of moyamoya disease.(A) An anterior-posterior and lateral views of left internal carotid angiography in a 9-year-old child with moyamoya disease (right) and an 8-year-old control child (left). An occlusion with moyamoya vessels can be seen around the terminal portion of the internal carotid artery and proximal portions of the anterior cerebral artery and middle cerebral artery in the affected child. (B) Intimal hyperplasia in the middle cerebral artery from an autopsy of a 69-year-old case. Intimal hyperplasia (red arrowhead), atrophic media (red arrow) and winding internal elastic lamina (black arrow) can be seen with Elastica Masson staining, ×200.

Mentions: Moyamoya disease is an idiopathic disorder characterized by occlusive lesions in the supraclinoid internal carotid artery and its main branches in the circle of Willis. To compensate for the blood flow around the occlusive region, a fine vascular network develops that resembles “puffs of smoke” (Figure 1A) [1]. The unique appearance of moyamoya vessels described by Suzuki and Takaku in 1969 [2] spurred international recognition of moyamoya disease [MIM 607151] (Online Mendelian Inheritance in Man in Appendix S1). Moyamoya disease occurs worldwide [3], but its prevalence is highest in East Asian countries, including Japan (1 in 10,000), Korea and China [4], [5]. It is known to cause stroke in neonates and children, and therefore pathological clues for early diagnosis and novel therapeutic approaches are needed [6].


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)

Clinical features of moyamoya disease.(A) An anterior-posterior and lateral views of left internal carotid angiography in a 9-year-old child with moyamoya disease (right) and an 8-year-old control child (left). An occlusion with moyamoya vessels can be seen around the terminal portion of the internal carotid artery and proximal portions of the anterior cerebral artery and middle cerebral artery in the affected child. (B) Intimal hyperplasia in the middle cerebral artery from an autopsy of a 69-year-old case. Intimal hyperplasia (red arrowhead), atrophic media (red arrow) and winding internal elastic lamina (black arrow) can be seen with Elastica Masson staining, ×200.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140517&req=5

pone-0022542-g001: Clinical features of moyamoya disease.(A) An anterior-posterior and lateral views of left internal carotid angiography in a 9-year-old child with moyamoya disease (right) and an 8-year-old control child (left). An occlusion with moyamoya vessels can be seen around the terminal portion of the internal carotid artery and proximal portions of the anterior cerebral artery and middle cerebral artery in the affected child. (B) Intimal hyperplasia in the middle cerebral artery from an autopsy of a 69-year-old case. Intimal hyperplasia (red arrowhead), atrophic media (red arrow) and winding internal elastic lamina (black arrow) can be seen with Elastica Masson staining, ×200.
Mentions: Moyamoya disease is an idiopathic disorder characterized by occlusive lesions in the supraclinoid internal carotid artery and its main branches in the circle of Willis. To compensate for the blood flow around the occlusive region, a fine vascular network develops that resembles “puffs of smoke” (Figure 1A) [1]. The unique appearance of moyamoya vessels described by Suzuki and Takaku in 1969 [2] spurred international recognition of moyamoya disease [MIM 607151] (Online Mendelian Inheritance in Man in Appendix S1). Moyamoya disease occurs worldwide [3], but its prevalence is highest in East Asian countries, including Japan (1 in 10,000), Korea and China [4], [5]. It is known to cause stroke in neonates and children, and therefore pathological clues for early diagnosis and novel therapeutic approaches are needed [6].

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