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RNF213 as the major susceptibility gene for Chinese patients with moyamoya disease and its clinical relevance

Qian Zhang, Yaping Liu, Dong Zhang, Rong Wang, Yan Zhang, Shuo Wang, Lanbing Yu, Chaoxia Lu, Fang Liu, Jian Zhou, Xue Zhang, and Jizong Zhao

aneurysm (1.3% vs 7.9%, p = 0.123), dilation of anterior choroidal artery (56.0% vs 47.4%, p = 0.101), or Suzuki stage (p = 0.486) between the 2 groups. Discussion The results of this study indicate that RNF213 is the major susceptibility gene for Chinese MMD patients. Moreover, no disease-causing mutations were identified in ACTA2 , BRCC3, or GUCY1A3 . Compared with the rate in previous studies of Chinese MMD patients, a much higher frequency of the p.R4810K variant was observed in our study (31.4% vs 9.4%–23%). 18 , 29 , 30 We also showed a higher

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Absence of the RNF213 p.R4810K variant may indicate a severe form of pediatric moyamoya disease in Japanese patients

Shoko Hara, Maki Mukawa, Hiroyuki Akagawa, Thiparpa Thamamongood, Motoki Inaji, Yoji Tanaka, Taketoshi Maehara, Hidetoshi Kasuya, and Tadashi Nariai

Liu W , Morito D , Takashima S , Mineharu Y , Kobayashi H , Hitomi T , Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development . PLoS One . 2011 ; 6 ( 7 ): e22542 . 21799892 10.1371/journal.pone.0022542 3 Kamada F , Aoki Y , Narisawa A , Abe Y , Komatsuzaki S , Kikuchi A , A genome-wide association study identifies RNF213 as the first moyamoya disease gene . J Hum Genet . 2011 ; 56 ( 1 ): 34 – 40 . 21048783 10.1038/jhg.2010.132 4 Morimoto T , Mineharu Y

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Association between moyamoya syndrome and the RNF213 c.14576G>A variant in patients with neurofibromatosis Type 1

Ji Hoon Phi, Jung Won Choi, Moon-Woo Seong, Tackeun Kim, Youn Joo Moon, Joongyub Lee, Eun Jung Koh, Seul Ki Ryu, Tae Hee Kang, Jae Seung Bang, Chang Wan Oh, Sung Sup Park, Ji Yeoun Lee, Kyu-Chang Wang, and Seung-Ki Kim

aggressive phenotypes of this disease with earlier onsets and cerebral infarctions. 9 Interestingly, the RNF213 c.14576G>A variant is also associated with non-moyamoya cerebrovascular disease. 10 , 11 Therefore, it is possible that RNF213 functions as a common susceptibility gene not only for moyamoya disease, in which the effect of the genetic variation is most powerful, but also for other vascular diseases. We hypothesized that MMS develops in some susceptible individuals in NF-1 populations and that the RNF213 c.14576G>A variant might be a susceptibility gene

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Experimental animal models for moyamoya disease and treatment: a pathogenesis-oriented scoping review

Michael S. Rallo, Omar Akel, Akhilesh Gurram, and Hai Sun

to present with intracranial hemorrhage and signs of mass effect (e.g., headache and papilledema). 7 , 8 Although still poorly understood, recent elucidations into the pathogenesis of MMD have advanced our knowledge of disease etiology and progression. 9 Notably, genetic studies have identified ring finger protein 213 ( RNF213 ) as a susceptibility gene mutated in 95% and 73% of familial and nonfamilial cases, respectively. 10 , 11 Interestingly, a c.14576G>A variant has been isolated in which homozygosity confers earlier onset, more severe symptoms, and worse

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Importance of RNF213 polymorphism on clinical features and long-term outcome in moyamoya disease

Eun-Hee Kim, Mi-Sun Yum, Young-Shin Ra, Jun Bum Park, Jae Sung Ahn, Gu-Hwan Kim, Hyun Woo Goo, Tae-Sung Ko, and Han-Wook Yoo

, 6 , 24 , 31 ) and several susceptibility genes ( ACTA2 , RPTOR , PDGFRB , MMP3 , and TGFB1 2 , 3 , 15 , 16 ) related to MMD, the RING (Really Interesting New Gene) finger protein 213 gene (RNF213) is the only susceptibility gene for MMD identified by both genome-wide association studies and exome sequencing. RNF213 at locus 17q25.3 is 135.42 kb in size, has 69 exons, and encodes a zinc finger protein involved in protein-protein interactions. 7 , 17 , 18 , 21 , 28 Several single nucleotide polymorphisms (SNPs) in RNF213, including c.14576G>A (p.R4859K

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Prolonged/delayed cerebral hyperperfusion in adult patients with moyamoya disease with RNF213 gene polymorphism c.14576G>A (rs112735431) after superficial temporal artery–middle cerebral artery anastomosis

Ryosuke Tashiro, Miki Fujimura, Masahito Katsuki, Taketo Nishizawa, Yasutake Tomata, Kuniyasu Niizuma, and Teiji Tominaga

in perioperative management in the early postoperative period, 4 , 16–18 delayed intracerebral hemorrhage and prolonged/delayed manifestation of CHP are still major clinical issues. 13 , 19 , 20 However, the risk factors for prolonged/delayed CHP are unknown. The RING finger protein 213 ( RNF213 ) is an important susceptibility gene for MMD among East Asians, and its particular polymorphism c.14576G>A (rs112735431) was reported to be correlated with earlier disease onset and the severe form of MMD. 21–23 Conversely, a recent study suggested that

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Prolonged/delayed cerebral hyperperfusion in adult patients with moyamoya disease with RNF213 gene polymorphism c.14576G>A (rs112735431) after superficial temporal artery–middle cerebral artery anastomosis

Ryosuke Tashiro, Miki Fujimura, Masahito Katsuki, Taketo Nishizawa, Yasutake Tomata, Kuniyasu Niizuma, and Teiji Tominaga

perioperative management in the early postoperative period, 4 , 16–18 delayed intracerebral hemorrhage and prolonged/delayed manifestation of CHP are still major clinical issues. 13 , 19 , 20 However, the risk factors for prolonged/delayed CHP are unknown. The RING finger protein 213 ( RNF213 ) is an important susceptibility gene for MMD among East Asians, and its particular polymorphism c.14576G>A (rs112735431) was reported to be correlated with earlier disease onset and the severe form of MMD. 21–23 Conversely, a recent study suggested that this polymorphism does not

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A review of the pathogenesis of ankylosing spondylitis

Elias Dakwar, Jaypal Reddy, Fernando L. Vale, and Juan S. Uribe

✓ Ankylosing spondylitis (AS) is a chronic, progressive inflammatory rheumatic disease involving primarily the sacroiliac joints and the axial skeleton. The main clinical features are back pain and progressive stiffness of the spine. Oligoarthritis of the hips and shoulders, enthesopathy, and anterior uveitis are common, and involvement of the heart and lungs is rare. The current understanding of the pathogenesis of this disorder is limited. Despite the strong association between human leukocyte antigen B27 (HLA-B27) and susceptibility to AS reported over the past 30 years, the exact pathogenic role of HLA-B27 in AS and other spondyloarthropathies has yet to be determined. The authors present a review of the literature pertaining to the pathogenesis of AS over the past several decades.

Ankylosing spondylitis is a polygenic disorder, with HLA-B27 playing a critical causative role in its pathogenesis. Animal studies of the immunobiology of HLA-B27 have provided significant insight into the pathogenic role of HLA-B27. The search for the antigenic peptide to support the “arthritogenic peptide” hypothesis has been disappointing. Over the past decade there has been increasing interest in the critical role of the misfolding and unfolded protein response of the heavy chain HLA-B27 in the modulation of the inflammatory response. Although there have been significant new findings in the understanding of the pathogenesis of AS, the exact mechanisms have yet to be identified. There is considerable optimism that additional susceptibility genes, predisposing factors, and regulators of the inflammatory process will be identified that will provide avenues for future treatment.

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Screening for brain aneurysm in the Familial Intracranial Aneurysm study: frequency and predictors of lesion detection

Robert D. Brown JR., John Huston III, Richard Hornung, DR.P.H., Tatiana Foroud, David F. Kallmes, Dawn Kleindorfer, Irene Meissner, Daniel Woo, Laura Sauerbeck, Joseph Broderick, and for the Familial Intracranial Aneurysm (FIA) Investigators

Object

Approximately 20% of patients with an intracranial saccular aneurysm report a family history of intracranial aneurysm (IA) or subarachnoid hemorrhage. A better understanding of predictors of aneurysm detection in familial IA may allow more targeted aneurysm screening strategies.

Methods

The Familial Intracranial Aneurysm (FIA) study is a multicenter study, in which the primary objective is to define the susceptibility genes related to the formation of IA. First-degree relatives (FDRs) of those affected with IA are offered screening with magnetic resonance (MR) angiography if they were previously unaffected, are ≥ 30 years of age, and have a history of smoking and/or hypertension. Independent predictors of aneurysm detection on MR angiography were determined using the generalized estimating equation version of logistic regression.

Results

Among the first 303 patients screened with MR angiography, 58 (19.1%) had at least 1 IA, including 24% of women and 11.7% of men. Ten (17.2%) of 58 affected patients had multiple aneurysms. Independent predictors of aneurysm detection included female sex (odds ratio [OR] 2.46, p = 0.001), pack-years of cigarette smoking (OR 3.24 for 20 pack-years of cigarette smoking compared with never having smoked, p < 0.001), and duration of hypertension (OR 1.26 comparing those with 10 years of hypertension to those with no hypertension, p = 0.006).

Conclusions

In the FIA study, among the affected patients' FDRs who are > 30 years of age, those who are women or who have a history of smoking or hypertension are at increased risk of suffering an IA and should be strongly considered for screening.

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Experimental animal models for the study of moyamoya disease

Vijay Letchuman, Leonel Ampie, Panagiotis Mastorakos, Daniel M. S. Raper, Ryan T. Kellogg, and Min S. Park

control mice. Of note, the experimental model was successful in mimicking the moyamoya-like vasculopathy seen in Suzuki stage I MMD. Although this study was conducted as an exploratory study with few animals and within a short timeframe, it provides the first experimental animal model created through surgical interventions specific for moyamoya vasculopathies. Genetic Techniques for Moyamoya Model Development The RNF213 gene, also known as the MMD susceptibility gene, encodes the ring finger domain, which, through E3 ubiquitin-protein ligase activity