Caveolin-1, Ring finger protein 213, and endothelial function in Moyamoya disease

Background Moyamoya disease is a unique cerebrovascular occlusive disease of unknown etiology. Ring finger protein 213 ( RNF213) was identified as a susceptibility gene for Moyamoya disease in East Asian countries. However, the pathogenesis of Moyamoya disease remains unclear. Methods We prospectively analyzed clinical data for 139 patients with Moyamoya disease (108 bilateral Moyamoya disease, 31 unilateral Moyamoya disease), 61 patients with intracranial atherosclerotic stroke, and 68 healthy subjects. We compared the genetic ( RNF213 variant) and protein biomarkers for caveolae (caveolin-1), angiogenesis (vascular endothelial growth factor (VEGF) and receptor (VEGFR2), and antagonizing cytokine (endostatin)) and endothelial dysfunction (asymmetric dimethylarginine (ADMA), and nitric oxide and its metabolites (nitrite and nitrate)) between patients with Moyamoya disease and intracranial atherosclerotic stroke. We then performed path analysis to evaluate whether a certain protein biomarker mediates the association between genes and Moyamoya disease. Results Caveolin-1 level was decreased in patients with Moyamoya disease and markedly decreased in RNF213 variant carriers. Circulating factors such as VEGF and VEGFR2 did not differ among the groups. Markers for endothelial dysfunction were significantly higher in patients with intracranial atherosclerotic stroke but normal in those with Moyamoya disease. Path analysis showed that the presence of the RNF213 variant was associated with caveolin-1 levels that could lead to Moyamoya disease. The level of combined marker of Moyamoya disease (caveolin-1) and intracranial atherosclerotic stroke (ADMA, an endothelial dysfunction marker) predicted Moyamoya disease with good sensitivity and specificity. Conclusion Our results suggest that Moyamoya disease is a caveolae disorder but is not related to endothelial dysfunction or dysregulation of circulating cytokines.

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Abstract WP280: Caveolin-1, Ring Finger Protein 213, and Endothelial Function in Moyamoya Disease

Stroke ◽

10.1161/str.47.suppl_1.wp280 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Jong-Won Chung ◽

Suk Jae Kim ◽

Jaechun Hwang ◽

Mi Ji Lee ◽

Hanna Choe ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Path Analysis ◽

Moyamoya Disease ◽

Susceptibility Gene ◽

Ring Finger ◽

Unknown Etiology ◽

Ring Finger Protein ◽

Protein Biomarkers ◽

Caveolin 1 ◽

Finger Protein

Background: Moyamoya disease (MMD) is a unique cerebrovascular occlusive disease of unknown etiology. Ring finger protein 213 (RNF213) was identified as a susceptibility gene for MMD in East Asian. However, the pathogenesis of MMD is still unclear. Methods: We prospectively analyzed clinical data for 139 patients with MMD (108 definite MMD, 31 probable MMD) and 61 patients with intracranial atherosclerotic stroke (ICAS), and 68 healthy subjects. We compared the genetic (RNF213 variant) and protein biomarkers for caveolae (caveolin-1), angiogenesis (vascular endothelial growth factor [VEGF] and receptor [VEGFR2], and antagonizing cytokine [endostatin]) and endothelial dysfunction (asymmetric dimethylarginine [ADMA], nitric oxide and its metabolites [nitrite and nitrate]), between patients with MMD and ICAS. We then performed the path analysis to evaluate whether a certain protein biomarker mediates the association the genetic and MMD. Results: Caveolin-1 level was decreased in patients with MMD and this level was markedly decreased in RNF213 variant carriers. Circulating factor such as VEGF and receptor were not different among the groups. Markers for endothelial dysfunction were significantly higher in patients with ICAS, but normal in MMD. The path analysis showed that the presence of the RNF213 variant was associated with caveolin-1 level that led to MMD. The level of combined marker of MMD (caveolin-1) and ICAS (ADMA, marker for endothelial dysfunction) predicted MMD with a good sensitivity and specificity. Conclusions: Our results indicate that MMD is primarily caveolae disorder, dysregulation of endothelial vesicular trafficking and signal transduction, but not related to endothelial dysfunction or dysregulation of circulating cytokines.

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Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function

Stroke ◽

10.1161/strokeaha.120.032691 ◽

2022 ◽

Author(s):

Vincent Roy ◽

Jay P. Ross ◽

Rémy Pépin ◽

Sergio Cortez Ghio ◽

Alyssa Brodeur ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Blood Brain Barrier ◽

Moyamoya Disease ◽

Susceptibility Gene ◽

Ring Finger ◽

Brain Barrier ◽

Ring Finger Protein ◽

Finger Protein ◽

Blood Brain

Background: Variants in the ring finger protein 213 ( RNF213 ) gene are known to be associated with increased predisposition to cerebrovascular diseases development. Genomic studies have identified RNF213 as a major risk factor of Moyamoya disease in East Asian descendants. However, little is known about the RNF213 (ring finger protein 213) biological functions or its associated pathogenic mechanisms underlying Moyamoya disease. Methods: To investigate RNF213 loss-of-function effect in endothelial cell, stable RNF213-deficient human cerebral endothelial cells were generated using the CRISPR-Cas9 genome editing technology. Results: In vitro assays, using RNF213 knockout brain endothelial cells, showed clear morphological changes and increased blood-brain barrier permeability. Downregulation and delocalization of essential interendothelial junction proteins involved in the blood-brain barrier maintenance, such as PECAM-1 (platelet endothelial cell adhesion molecule-1), was also observed. Brain endothelial RNF213-deficient cells also showed an abnormal potential to transmigration of leukocytes and secreted high amounts of proinflammatory cytokines. Conclusions: Taken together, these results indicate that RNF213 could be a key regulator of cerebral endothelium integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease. This study also further reinforces the importance of blood-brain barrier integrity in the development of Moyamoya disease and other RNF213-associated diseases.

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The Impact of Moyamoya Disease and RNF213 Mutations on the Spectrum of Plasma Protein and MicroRNA

Journal of Clinical Medicine ◽

10.3390/jcm8101648 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1648 ◽

Cited By ~ 1

Author(s):

Ming-Jen Lee ◽

Shannon Fallen ◽

Yong Zhou ◽

David Baxter ◽

Kelsey Scherler ◽

...

Keyword(s):

Moyamoya Disease ◽

Plasma Protein ◽

Ring Finger ◽

Ring Finger Protein ◽

Absolute Quantitation ◽

Small Vessels ◽

Finger Protein ◽

Isobaric Tags ◽

Ischemic Attack ◽

The Impact

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by occlusion of bilateral internal carotid and intracerebral arteries with the compensatory growth of fragile small vessels. MMD patients develop recurrent infarctions in the basal ganglia and subcortical regions. Symptoms include transient ischemic attack or stroke, seizures, and headaches, which may occur suddenly or in a stepwise progression. Mutations in Ring Finger Protein 213 (RNF213), a Zinc ring finger protein, have been identified in some MMD patients but the etiology of MMD is still largely unknown. To gain insight into the pathophysiology of MMD, we characterized the impact of the RNF213 mutations on plasma protein and RNA profiles. Isobaric tags for relative and absolute quantitation and proximity extension assay were used to characterize the plasma proteome. Next generation sequencing-based small RNAseq was used to analyze the cell-free small RNAs in whole plasma and RNA encapsulated in extracellular vesicles. The changes of miRNAs and proteins identified are associated with signaling processes including angiogenesis and immune activities which may reflect the pathology and progression of MMD.

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Role of Ring Finger Protein 213 in Moyamoya Disease

Chinese Medical Journal ◽

10.4103/0366-6999.191824 ◽

2016 ◽

Vol 129 (20) ◽

pp. 2497-2501 ◽

Cited By ~ 6

Author(s):

Yong-Gang Ma ◽

Qian Zhang ◽

Le-Bao Yu ◽

Ji-Zong Zhao

Keyword(s):

Moyamoya Disease ◽

Ring Finger ◽

Ring Finger Protein ◽

Finger Protein

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

Scientific Reports ◽

10.1038/s41598-021-01623-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yasuo Murai ◽

Eitaro Ishisaka ◽

Atsushi Watanabe ◽

Tetsuro Sekine ◽

Kazutaka Shirokane ◽

...

Keyword(s):

Carotid Artery ◽

Internal Carotid Artery ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Internal Carotid ◽

Accurate Determination ◽

Susceptibility Gene ◽

Ring Finger ◽

Ring Finger Protein ◽

Finger Protein

AbstractThe 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.

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