Filamin A Variant as a Possible Second-Hit Gene Promoting Moyamoya Disease–like Vascular Formation Associated With RNF213 p.R4810K Variant

Discussion

In this study, we clearly demonstrated that the patient inherited the RNF213 variant from her father and the FLNA variant from her mother (Figures 1 and 2). Because only the patient having the 2 variants manifested symptomatic PNH accompanied by Ehlers-Danlos–like symptoms and MMD-like vascular formation, each gene abnormality alone may cause only subtle phenotypic changes while their coexistence may mutually amplify them. It is important that the direct interaction between the 2 molecules is known: Filamin A undergoes RNF213-mediated ubiquitination and proteasomal degradation for its turnover.² Because ligase activity of RNF213 p.R4810K is decreased, the abnormal filamin A may accumulate in cells expressing RNF213 and filamin A.² Filamin A regulates cellular mobility through its dimerization and interaction with various molecules, including integrin, via its C-terminal portion, which further interacts with extracellular matrix proteins, while the N-terminal portion participates in actin-binding and ubiquitination (Figure 3).⁴ The C-terminally truncated filamin A may impair the migration of newborn neurons from the periventricular zone to the cortex during development, resulting in PNH. In adults, the filamin A variant may cause flow-mediated or pressure-mediated hypermobility of vascular smooth muscle cells, resulting in increased calcium influx through the mechanosensor channel, thereby inducing arterial remodeling and stenosis of cerebral arteries (Figure 3).⁵

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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.

We cannot completely exclude that the FLNA abnormality coexists independently of MMD in the patient. Even if it is related to MMD, it may be uncommon in MMD. There has been 1 case series that briefly described a 3-year-old male patient having an FLNA abnormality among 54 patients with MMD.⁶ Although FLNA variants presenting with PNH often show X-linked dominant inheritance, we should note that some FLNA variants are transmitted in X-linked recessive mode and their phenotypic changes may be affected by X-inactivation.⁷

Collectively, we identify FLNA as a possible second-hit gene that may affect MMD-like vascular formation in an individual having the RNF213 p.R4810K variant. RNF213 also functions as an E3-ubiquitin ligase for itself and other molecules, including NFAT.² Moreover, RNF213 contributes to lipid metabolism.² Thus, besides FLNA, there may be other RNF213-related genes whose abnormality can elicit MMD-like vascular formation associated with the RNF213 p.R4810K variant.