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

もやもや病感受性遺伝子の特定とその機能についての発見. 京都大学プレスリリース. 2011-7-21.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

[Current knowledge on the genetic factors involved in moyamoya disease].

Moyamoya disease (MMD) is characterized by progressive stenosis and occlusion of the terminal portion of the bilateral carotid arteries as well as arterial collateral vessels. The etiology of MMD, however, remains unknown. Several pieces of evidence suggest the involvement of genetic factors in MMD: over 10% of MMD patients have affected blood relatives; concordance in the affection status has been proven in 80% of identical twins; and there is an ethnic predisposition to MMD, the incidence of the disease being the highest in the Asian population. With regard to genetic factor (s), transmission of MMD does not follow the classic Mendelian law, i.e., skipping of a generation and discordance in identical twins, thereby indicating that genetic influence is likely to determine the susceptibility to MMD. This study aimed to overview the recent findings related to the genetic determinants in MMD and to provide research perspectives for the next decade. Pathophysiological investigations at molecular levels have uncovered the upregulation of various growth and stress response factors that are associated with angiogenesis in occlusive cerebral arteries

Impact of Diastolic Vessel Restriction on Quality of Life in Symptomatic Myocardial Bridging Patients Treated With Surgical Unroofing: Preoperative Assessments With Intravascular Ultrasound and Coronary Computed Tomography Angiography

Background: Despite optimal medical therapy, a myocardial bridge (MB) can cause life-limiting symptoms in a subset of patients. While surgical unroofing has been shown to improve MB-derived refractory angina, diagnostic indices of clinical symptoms and predictors of improvement following surgery are yet to be elucidated. Methods: To identify determinants of preoperative symptoms and their improvement following the surgery, preoperative intravascular ultrasound (IVUS) and coronary computed tomography angiography were evaluated in 111 patients with symptomatic MB who underwent surgical unroofing. The primary outcome was the Seattle Angina Questionnaire summary score (the average of physical limitation, angina frequency, and quality of life scores). In addition to standard anatomic variables of an MB, degrees of extrinsic vessel restriction at end-diastole and end-systole were evaluated by IVUS using the ratio of measured vessel area and interpolated reference at the maximum compression site. The diastolic restriction was also evaluated by coronary computed tomography angiography as the maximum lumen area stenosis within the MB segment. Results: Even during diastole, IVUS revealed vessel restriction in 87% of the patients. Among the variables evaluated, vessel restriction was the strongest parameter correlating with the preoperative Seattle Angina Questionnaire summary score, particularly when assessed in diastole ( P &lt;0.0001 in IVUS, P =0.006 in coronary computed tomography angiography). The diastolic restriction by IVUS also showed a weak, but significant correlation with improvement in Seattle Angina Questionnaire summary score 6 months after surgery ( P =0.004). Conclusions: Restricted arterial relaxation in diastole, rather than the degree of systolic compression or extent of an MB, seems to be the primary determinant of clinical symptoms and improvement in quality of life following surgical unroofing. </jats:sec