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

Yasuhito Ikeuchi; Jiro Kitayama; Noriyuki Sahara; Takuya Okata; Noriko Miyake; Naomichi Matsumoto; Takanari Kitazono; Tetsuro Ago

doi:10.1212/NXG.0000000000200017

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

Neurol Genet. 2022 Sep 9;8(5):e200017. doi: 10.1212/NXG.0000000000200017. eCollection 2022 Oct.

Authors

Yasuhito Ikeuchi¹, Jiro Kitayama¹, Noriyuki Sahara¹, Takuya Okata¹, Noriko Miyake¹, Naomichi Matsumoto¹, Takanari Kitazono¹, Tetsuro Ago¹

Affiliation

¹ Department of Neurology (Y.I., J.K., N.S., T.O.), Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan; Department of Human Genetics (N. Miyake, N. Matsumoto), Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Human Genetics (N. Miyake), Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Department of Medicine and Clinical Science (T.K., T.A.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Abstract

Background and objective: The objective of this case report was to identify a second-hit gene that may promote Moyamoya disease (MMD)-like vascular formation in an individual having the RNF213 p.R4810K variant.

Methods: We performed magnetic resonance imaging and genetic analyses of RNF213 and FLNA in a 21-year-old woman, who showed Ehlers-Danlos-like symptoms and developed a first-ever unprovoked seizure, and of her healthy parents.

Results: We identified bilateral periventricular nodular heterotopia (PNH) as the cause of seizures and MMD-like vascular formation in the patient. The patient had the RNF213 p.R4810K variant. Exome analysis identified c.4868delG in the X-linked FLNA gene encoding filamin A p.G1623V fs*41, which could explain PNH and Ehlers-Danlos-like symptoms. Her mother had the same FLNA variant and had asymptomatic bilateral PNH, whereas her father had the RNF213 variant and had normal cerebrovascular structure.

Discussion: The family study suggested that the FLNA variant promoted MMD-like vascular formation in a patient having the RNF213 variant, while the RNF213 variant amplified the phenotypic changes elicited by the FLNA abnormality. Collectively, we identified a gene abnormality in filamin A, a target of RNF213-mediated proteasomal degradation, that may promote MMD-like vascular formation as a possible second-hit gene in individuals having the RNF213 p.R4810K variant.