Article Figures & Data
Figures
- Figure 1 Pedigree and Neuroimaging
(Patient) Bilateral PNH (yellow arrows) on T2-weighted images and narrowing of the bilateral internal carotid artery terminal portion accompanied by MMD-like vascular formation on MRA. Hypermobility of the thumb is shown. (Mother) Asymptomatic bilateral PNH (yellow arrows) without MMD-like vascular formation and Ehlers-Danlos–like symptoms. (Father) No abnormalities on MRI/MRA. MMD = Moyamoya disease; MRA = magnetic resonance angiography; PNH = periventricular nodular heterotopia.
- Figure 2 Sequencing of RNF213 and FLNA
(A) A single nucleotide substitution of G to A at 14429 in the RNF213 gene (c.14429G>A, p.Arg4810Lys) is identified in the patient and her father. (B) A single nucleotide deletion at 4868 in the FLNA gene (c.4868delG), leading to p.Gly1623Val fs*41 is identified in the patient and her mother. Fw = forward; Rv = reverse.
- Figure 3 Putative Mechanism Underlying Hypermobility of Vascular Smooth Muscle Cells Leading to Arterial Remodeling in the Patient Having RNF213 p.R4810K and FLNA p.G1623V fs*41
(A) Filamin A forms a homodimer and interacts directly with integrin via its C-terminal portion, while its N-terminal portion interacts with filamentous actin (F-actin) and undergoes RNF213-mediated ubiquitination for its turnover. Integrin interacts with ECM, thereby preventing hypermobilization of vascular smooth muscle cells. (B) The filamin A variant with p.G1623V fs*41, which lacks its C-terminal portion, can neither form a homodimer nor interact with integrin, thereby causing hypermobilization of vascular smooth muscle cells. The hypermobilization of the cells increases the calcium influx through the mechanosensor channel Piezo1 that leads to arterial remodeling. Because the RNF213 p.R4810K variant has a decreased ubiquitin ligase activity that is required for the degradation and turnover of filamin A, the filamin A variant would accumulate and amplify its phenotypic changes as a dominant-negative form in the cells expressing the RNF213 p.R4810K variant. ECM = extracellular matrix proteins.
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