Sibling cases of moyamoya disease having homozygous and heterozygous c.14576G&gt;A variant in RNF213 showed varying clinical course and severity

Miyatake, Satoko; Touho, Hajime; Miyake, Noriko; Ohba, Chihiro; Doi, Hiroshi; Saitsu, Hirotomo; Taguri, Masataka; Morita, Satoshi; Matsumoto, Naomichi

doi:10.1038/jhg.2012.105

Cited by 39 publications

(37 citation statements)

References 16 publications

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“…Of note, in these studies, the p.R4810K variant was found in 1-2% of Japanese controls and in 0.4% of Chinese Han controls, and therefore, it should be considered as a MMD susceptibility variant rather than a MMD causing variant. It was also suggested that presence of the p.R4810K variant, when present in an homozygous state, was associated with an earlier onset and a more severe disease course, suggesting a value of this variant as a biomarker for predicting prognosis [83,86,87] .…”

Section: Genome-wide Linkage Studiesmentioning

confidence: 99%

Research Progresses in Understanding the Pathophysiology of Moyamoya Disease

et al. 2016

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Background: The pathogenesis of moyamoya disease (MMD) is still unknown. The detection of inflammatory molecules such as cytokines, chemokines and growth factors in MMD patients' biological fluids supports the hypothesis that an abnormal angiogenesis is implicated in MMD pathogenesis. However, it is unclear whether these anomalies are the consequences of the disease or rather causal factors as well as these mechanisms remain insufficient to explain the pathophysiology of MMD. The presence of a family history in about 9-15% of Asian patients, the highly variable incidence rate between different ethnic and sex groups and the age of onset support the role of genetic factors in MMD pathogenesis. However, although some genetic loci have been associated with MMD, few of them have been replicated in independent series. Recently, RNF213 gene was shown to be strongly associated with MMD occurrence with a founder effect in East Asian patients. However, the mechanisms leading from RNF213 mutations to MMD clinical features are still unknown. Summary: The research on pathogenic mechanism of MMD is in its infancy. MMD is probably a complex and heterogeneous disorder, including different phenotypes and genotypes, in which more than a single factor is implicated. Key Message: Since the diagnosis of MMD is rapidly increasing worldwide, the development of more efficient stratifying risk systems, including both clinical but also biological drivers became imperative to improve our ability of predict prognosis and to develop mechanism-tailored interventions.

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Section: Genome-wide Linkage Studiesmentioning

confidence: 99%

Research Progresses in Understanding the Pathophysiology of Moyamoya Disease

et al. 2016

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“…The gene encodes a novel huge 591-kDa protein. Rare missense variants in its coding region significantly increase the risk of the disease and are associated with vascular abnormalities141516171819. Its cloning and characterization revealed that the huge protein contains enzymatically active Walker A and B motifs and a RING (really interesting new gene) finger domain14.…”

mentioning

confidence: 99%

Moyamoya disease-associated protein mysterin/RNF213 is a novel AAA+ ATPase, which dynamically changes its oligomeric state

Morito

Nishikawa

Hoseki³

et al. 2014

Sci Rep

122

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Moyamoya disease is an idiopathic human cerebrovascular disorder that is characterized by progressive stenosis and abnormal collateral vessels. We recently identified mysterin/RNF213 as its first susceptibility gene, which encodes a 591-kDa protein containing enzymatically active P-loop ATPase and ubiquitin ligase domains and is involved in proper vascular development in zebrafish. Here we demonstrate that mysterin further contains two tandem AAA+ ATPase modules and forms huge ring-shaped oligomeric complex. AAA+ ATPases are known to generally mediate various biophysical and mechanical processes with the characteristic ring-shaped structure. Fluorescence correlation spectroscopy and biochemical evaluation suggested that mysterin dynamically changes its oligomeric forms through ATP/ADP binding and hydrolysis cycles. Thus, the moyamoya disease-associated gene product is a unique protein that functions as ubiquitin ligase and AAA+ ATPase, which possibly contributes to vascular development through mechanical processes in the cell.

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“…Miyatake et al [7] reported that patients with the homozygous c.14576G>A variant in the RNF213 gene showed significantly earlier age at onset and wider vasculopathy in the brain, which resulted in a more severe form of MMD. In another study, the researchers [8] reported that sibling patients of MMD have homozygous and heterozygous c.14576G>A variant in RNF213 with different clinical presentation and discussed its genetic impact on clinical phenotype in members with similar genetic background. However, Hamada et al [2] reported that pediatric sibling patients of MMD show a tendency towards similar onset age and similar clinical courses and angiographic findings.…”

Section: Discussionmentioning

confidence: 95%

“…Furthermore, patients having this variant were found to correlate with significantly earlier disease onset and a more severe form of MMD [7]. In addition, the homozygous c.14576G>A genotype exhibits a more severe type of MMD with a poor prognosis when compared with heterozygotes [7,8].…”

Section: Etiologymentioning

confidence: 96%