Pathological Investigation on RNF213: Animal Models of Rnf213-Knockout and Knock-in Mice

Abstract

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by a progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Although its etiology is undetermined, recent genome-wide and locus-specific association studies identified RNF213 as an important susceptibility gene for MMD among East Asian population. A polymorphism in c.14576G>A in RNF213 was evident in almost all of the familial patients with MMD and 80% of sporadic cases, but the exact role of RNF213 polymorphism in the development of MMD remains unknown. To answer this question, we generated genetically engineered mice lacking Rnf213 by homologous recombination (Rnf213-knockout mice), as well as Rnf213-knock-in mice expressing a missense mutation in mouse Rnf213, p. R4828K, corresponding to human RNF213, p. R4859K, in MMD patients. Although both mice did not spontaneously develop MMD up to 64 weeks of age as shown by high-resolution magnetic resonance angiography and carbon black injection analysis of the circle of Willis, the biological response of these mice under a variety of insults, such as ischemia or immunological stimuli, provided new insights for the pathogenesis of this rare entity.