A genome-wide association study identifies RNF213 as the first Moyamoya disease gene

Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
Journal of Human Genetics (Impact Factor: 2.46). 11/2010; 56(1):34-40. DOI: 10.1038/jhg.2010.132
Source: PubMed


Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. Although ∼ 15% of MMD cases are familial, the MMD gene(s) remain unknown. A genome-wide association study of 785,720 single-nucleotide polymorphisms (SNPs) was performed, comparing 72 Japanese MMD patients with 45 Japanese controls and resulting in a strong association of chromosome 17q25-ter with MMD risk. This result was further confirmed by a locus-specific association study using 335 SNPs in the 17q25-ter region. A single haplotype consisting of seven SNPs at the RNF213 locus was tightly associated with MMD (P = 5.3 × 10(-10)). RNF213 encodes a really interesting new gene finger protein with an AAA ATPase domain and is abundantly expressed in spleen and leukocytes. An RNA in situ hybridization analysis of mouse tissues indicated that mature lymphocytes express higher levels of Rnf213 mRNA than their immature counterparts. Mutational analysis of RNF213 revealed a founder mutation, p.R4859K, in 95% of MMD families, 73% of non-familial MMD cases and 1.4% of controls; this mutation greatly increases the risk of MMD (P = 1.2 × 10(-43), odds ratio = 190.8, 95% confidence interval = 71.7-507.9). Three additional missense mutations were identified in the p.R4859K-negative patients. These results indicate that RNF213 is the first identified susceptibility gene for MMD.

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    • "Among them, autoimmune response could be the strongest candidate as the secondary insult to develop moyamoya disease, in light of the high prevalence of Graves' disease; autoimmune hyperthyroidism among East Asia patients with moyamoya disease (Kim et al. 2010). Alternatively, RNF213 polymorphism could directly affect autoimmunity and thus contribute to the development of moyamoya disease, because RNF213 is predominantly expressed in white blood cells and spleen (Kamada et al. 2011). "
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    ABSTRACT: Moyamoya disease is a chronic cerebrovascular disease with unknown etiology, which is characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery and an abnormal vascular network formation at the base of the brain. Moyamoya disease is known to have unique and dynamic nature to convert the vascular supply for the brain from internal carotid (IC) system to the external carotid (EC) system, as indicated by Suzuki's angiographic staging established in 1969. Insufficiency of this 'IC-EC conversion system' may result in cerebral ischemia, as well as in intracranial hemorrhage from inadequate collateral vascular network, both of which represent the clinical presentation of moyamoya disease. Therefore, surgical revascularization by extracranial-intracranial bypass is the preferred procedure for moyamoya disease to complement 'IC-EC conversion' and thus to avoid cerebral infarction and/or intracranial hemorrhage. Long-term outcome of revascularization surgery for moyamoya disease is favorable, but rapid increase in cerebral blood flow on the affected hemisphere could temporarily cause unfavorable phenomenon such as cerebral hyperperfusion syndrome. We would review the current status of revascularization surgery for moyamoya disease based on its basic pathology, and sought to discuss the significance of measuring cerebral blood flow in the acute stage and intensive perioperative management.
    Preview · Article · May 2015 · The Tohoku Journal of Experimental Medicine
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    • "It is thought that HLA can either control susceptibility of disease or other genes responsible for the disease could have linkage disequilibrium with Metab Brain Dis mutated HLA allele (Inoue et al. 2000). In 2011, Kamada and his team identified RNF213 as the first Moyamoya disease gene (Kamada et al. 2011). A genome wide association study using 72 Moyamoya disease patients and 45 control patients identified a locus on chromosome 17q25 with strong association to the disease. "
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    ABSTRACT: Neurovascular diseases are among the leading causes of mortality and permanent disability due to stroke, aneurysm, and other cardiovascular complications. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and Marfan syndrome are two neurovascular disorders that affect smooth muscle cells through accumulation of granule and osmiophilic materials and defective elastic fiber formations respectively. Moyamoya disease, hereditary hemorrhagic telangiectasia (HHT), microcephalic osteodysplastic primordial dwarfism type II (MOPD II), and Fabry's disease are disorders that affect the endothelium cells of blood vessels through occlusion or abnormal development. While much research has been done on mapping out mutations in these diseases, the exact mechanisms are still largely unknown. This paper briefly introduces the pathogenesis, genetics, clinical symptoms, and current methods of treatment of the diseases in the hope that it can help us better understand the mechanism of these diseases and work on ways to develop better diagnosis and treatment.
    Full-text · Article · Apr 2015 · Metabolic Brain Disease
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    • "In the near future, the pathogenesis of MMD might be determined by genetic analyses. Identification of the relevant genes may be very promising for the development of novel gene therapies and prevent the occurrence of MMD [2], [ 21], [ 22]. "
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    ABSTRACT: Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches. However, the etiology of this rare disease remains unknown. Serum microRNA (miRNA) profiles have been screened to identify novel biomarkers of prognostic values. Here, we identified serum miRNAs that might play an important role in the pathogenesis of MMD. A genome-wide miRNA array analysis of two pooled serum samples from patients with MMD and controls revealed 94 differentially expressed serum miRNAs, including 50 upregulated and 44 downregulated miRNAs. In an independent MMD cohort, real-time PCR confirmed that miR-106b, miR-130a and miR-126 were significantly upregulated while miR-125a-3p was significantly downregulated in serum. GO analysis showed that the differentially expressed serum miRNAs were enriched in metabolic processes, transcription and signal transduction. Pathway analysis showed that the most enriched pathway was mTOR signaling pathway with 16 potential, functional targets. Finally, we found that 16 and 13 aberrant serum miRNAs coordinately inhibited RNF213 and BRCC3 protein expression at the posttranscriptional level, respectively, resulting in defective angiogenesis and MMD pathogenesis. To our knowledge, this is the first study to identify a serum miRNA signature in MMD. Modulation of the mechanism underlying the role of serum miRNAs in MMD is a potential therapeutic strategy and warrants further investigations.
    Full-text · Article · Aug 2014 · PLoS ONE
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