RNF213 gene polymorphism rs9916351 and rs8074015 significantly associated with moyamoya disease in Chinese population

Zhu, Bin; Liu, Xingju; Zhen, Xueke; Li, Xixi; Wu, Mingfen; Zhang, Yan; Zhao, Zhigang; Zhang, Dong; Zhao, Jizong

doi:10.21037/atm-20-1040

Cited by 11 publications

(8 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…19 Moreover, although contributing significantly to the genetic burden of MMD, the common variant risk factor RNF213 is represented predominantly in Japanese and other East Asian populations. 16,26,27 Therefore, a significant proportion of MMD remains genetically undefined, especially among the European population. 5,28 The sporadic nature of most MMD cases limits the utility of classic genetic approaches.…”

mentioning

confidence: 99%

DIAPH1 Variants in Non–East Asian Patients With Sporadic Moyamoya Disease

et al. 2021

View full text Add to dashboard Cite

IMPORTANCE Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals. OBJECTIVE To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk. DESIGN, SETTING, AND PARTICIPANTSA genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016)(2017)(2018)(2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort.MAIN OUTCOMES AND MEASURES Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue. RESULTSOf the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10 −6 ) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways.CONCLUSIONS AND RELEVANCE These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk...

show abstract

mentioning

confidence: 99%

DIAPH1 Variants in Non–East Asian Patients With Sporadic Moyamoya Disease

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Both were RNF213 c.14576G > A (p.R4859K, rs112735431). Subsequent studies 7 , 19 – 23 have also reported the RNF213 polymorphism in MMD, but there is a bias by country 20 . In fact, p.R4810K 22 , which has garnered attention as a susceptibility gene for MMD in East Asians other than p.R4859K, has been reported from Japan 24 , China 22 , 25 , 26 , and Korea 27 .…”

Section: Discussionmentioning

confidence: 99%

Ring finger protein 213 c.14576G>A mutation is not involved in internal carotid artery and middle cerebral artery dysplasia

Murai

Ishisaka

Watanabe

et al. 2021

Sci Rep

View full text Add to dashboard Cite

The ring finger protein 213 (RNF213) susceptibility gene has been detected in more than 80% of Japanese and Korean patients with moyamoya disease (MMD), a bilateral internal carotid artery (ICA) occlusion. Furthermore, RNF213 has been detected in more than 20% of East Asians with atherosclerotic ICA stenosis. In this study, we evaluated the frequency of RNF213 mutations in congenital occlusive lesions of the ICA system. This case series was conducted jointly at four university hospitals. Patients with a family history of MMD, quasi-MMD, or related diseases were excluded. Ten patients were diagnosed with abnormal ICA or middle cerebral artery (MCA) angiogenesis. Patients with neurofibromatosis were excluded. Finally, nine patients with congenital vascular abnormalities were selected; of these, five had ICA deficiency and four had twig-like MCA. The RNF213 c.14576G > A mutation was absent in all patients. Therefore, the RNF213 c.14576G > A mutation may not be associated with ICA and MCA congenital dysplasia—rare vascular anomalies making it difficult to study a large number of cases. However, an accumulation of cases is required for accurate determination. The results of this study may help differentiate congenital vascular diseases from MMD.

show abstract

“… 169 In a study using a Chinese population, rs9916351 and rs8074015 in RNF213 were demonstrated to be significantly associated with MA. 172 The RNF213 (p.R4810K) variant may predispose individuals of Asian descent living in the United States to MA. 173 Zhang et al 174 identified 27 rare RNF213 missense variants in 255 Chinese MA patients not found in 300 healthy controls.…”

Section: Genetic Biomarkers Of Moyamoya Angiopathymentioning

confidence: 99%

Genetic and Proteomic Contributions to the Pathophysiology of Moyamoya Angiopathy and Related Vascular Diseases

Dorschel

Wanebo

2021

TACG

View full text Add to dashboard Cite

This literature review describes the pathophysiological mechanisms of the current classes of proteins, cells, genes, and signaling pathways relevant to moyamoya angiopathy (MA), along with future research directions and implementation of current knowledge in clinical practice. Objective: This article is intended for physicians diagnosing, treating, and researching MA. Methods and Results: References were identified using a PubMed/Medline systematic computerized search of the medical literature from January 1, 1957, through August 4, 2020, conducted by the authors, using the key words and various combinations of the key words "moyamoya disease," "moyamoya syndrome," "biomarker," "proteome," "genetics," "stroke," "angiogenesis," "cerebral arteriopathy," "pathophysiology," and "etiology." Relevant articles and supplemental basic science articles published in English were included. Intimal hyperplasia, medial thinning, irregular elastic lamina, and creation of moyamoya vessels are the end pathologies of many distinct molecular and genetic processes. Currently, 8 primary classes of proteins are implicated in the pathophysiology of MA: gene-mutation products, enzymes, growth factors, transcription factors, adhesion molecules, inflammatory/ coagulation peptides, immune-related factors, and novel biomarker candidate proteins. We anticipate that this article will need to be updated in 5 years. Conclusion:It is increasingly apparent that MA encompasses a variety of distinct pathophysiologic conditions. Continued research into biomarkers, genetics, and signaling pathways associated with MA will improve and refine our understanding of moyamoya's complex pathophysiology. Future efforts will benefit from multicenter studies, familybased analyses, comparative trials, and close collaboration between the clinical setting and laboratory research.

show abstract

RNF213 gene polymorphism rs9916351 and rs8074015 significantly associated with moyamoya disease in Chinese population

Cited by 11 publications

References 23 publications

DIAPH1 Variants in Non–East Asian Patients With Sporadic Moyamoya Disease

DIAPH1 Variants in Non–East Asian Patients With Sporadic Moyamoya Disease

Ring finger protein 213 c.14576G>A mutation is not involved in internal carotid artery and middle cerebral artery dysplasia

Genetic and Proteomic Contributions to the Pathophysiology of Moyamoya Angiopathy and Related Vascular Diseases

Contact Info

Product

Resources

About