A genome-wide association study identifies RNF213 as the first Moyamoya disease gene.
ABSTRACT 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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Article: AAA proteins.[show abstract] [hide abstract]
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ABSTRACT: Increasing evidence points to a role for circulating endothelial progenitor cells, including populations of CD34-positive (CD34(+)) cells, in maintenance of cerebral blood flow. In this study, we investigated the link between the level of circulating CD34(+) cells and neovascularization at ischemic brain. Compared with control subjects, a remarkable increase of circulating CD34(+) cells was observed in patients with angiographic moyamoya vessels, although no significant change was observed in patients with major cerebral artery occlusion (or severe stenosis) but without moyamoya vessels. Our results suggest that the increased level of CD34(+) cells associated with ischemic stress is correlated with neovascularization at human ischemic brain.Journal of Cerebral Blood Flow & Metabolism 07/2008; 28(6):1086-9. · 5.40 Impact Factor
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ABSTRACT: To estimate an annual number of patients treated for Moyamoya disease in Japan and to describe the clinico-epidemiological features, a nationwide epidemiological survey was conducted in 1995. The study consisted of two questionnaires, which were distributed to departments randomly selected, of neurosurgery, neurology and pediatrics in hospitals throughout Japan. The first questionnaire inquired the number of the patients treated in 1994 and the second one detailed clinico-epidemiological information of each patient reported. Following major epidemiological findings emerged from the study: (a) The total annual number of patients treated for Moyamoya disease was estimated as 3900 (95% confidence interval (CI) 3500-4400) in Japan 1994, with the prevalence and incidence rates of 3.16 and 0.35 per 100,000 population, respectively; (b) the sex ratio (females to males) of the patients was 1.8; (c) the peak of age distribution of the patients was observed in 10-14 years old and a smaller peak in their forties; (d) the age at onset was under 10 years old in 47.8% of the patients, but some had developed the disease at the age of 25-49 years; (e) family history of Moyamoya disease was found in 10.0% of the patients; and (f) about 75% of the patients had normal activity of daily life or working ability even before treatment. The present findings were quite comparable with those obtained in the previous nationwide epidemiological survey in 1990.Clinical Neurology and Neurosurgery 11/1997; 99 Suppl 2:S1-5. · 1.23 Impact Factor