A new horizon of moyamoya disease and associated health risks explored through RNF213

Abstract

The cerebrovascular disorder moyamoya disease (MMD) was first described in 1957 in Japan, and is typically considered to be an Asian-specific disease. However, it is globally recognized as one of the major causes of childhood stroke. Although several monogenic diseases are known to be complicated by Moyamoya angiopathy, the ring finger protein 213 gene (RNF213) was identified as a susceptibility gene for MMD. RNF213 is unusual, because (1) it induces MMD with no other recognizable phenotypes, (2) the RNF213 p.R4810K variant is an Asian founder mutation common to Japanese, Korean and Chinese with carrier rates of 0.5-2% of the general population but a low penetrance, and (3) it encodes a relatively largest proteins with a dual AAA+ ATPase and E3 Ligase activities. In this review, we focus on the genetics and genetic epidemiology of RNF213, the pathology of RNF213 R4810K, and the molecular functions of RNF213, and also address the public health contributions to current unresolved issues of MMD. We also emphasize the importance of a more updated definition for MMD, of qualified cohort studies based on genetic epidemiology and an awareness of the ethical issues associated with genetic testing of carriers.

Keywords: Angiogenesis; Asian founder mutation; Hypoxia; Moyamoya disease; RNF213 R4810K.

Fig. 1

Moyamoya angiopathy. An identical twin first-born twin sister (II-1), who developed MMD at the age of 36 years, had stenosis in her anterior and middle cerebral arteries bilaterally and underwent surgery. The second-born twin sister (II-2) is represented with a solid quadrant. Magnetic resonance angiography (lower panels) was taken when they were 55 years old. Patient II-2 showed stenosis (arrows). Their mother (I-2) died when she was 71 years old from cerebral infarction. Her niece also developed MMD (II-3). Subjects I-3, II-1, II-2, and II-3 all shared the WT/R4810K genotype. We assumed the carrier status for I-2, I-3, and II-2 in our linkage analysis. Due to the rarity of the disease gene, we assumed that I-2 is a carrier of the MMD-associated gene. This pedigree is simplified from the original pedigree 14 [12]

Fig. 2

Variants shown are described previously [11, 12, 14, 15, 37, 39] (see details in Table 2). Variants in Asian and Caucasian patients are shown above and below the protein, respectively. The domain structure was based on [19]. AA amino acid, AAA+ ATPase associated with diverse cellular activities domain, RING ring finger domain

Fig. 3

Inhibition of angiogenesis by INFβ and lowered angiogenic activity of iPSECs established from controls and patients. iPSCs were established from controls and patients with MMD. Mature iPSECs were developed from iPSCs as reported by Hitomi et al. [24]. a Treatment with INFβ induced mRNA of RNF213 significantly. b Tube formation was lowered in patients. Treatment with INFβ inhibited tube formation for iPSEECs from patients. Cited from Kobayashi et al. [21]

Fig. 4

Lowered adaptive cerebral angiogenesis after exposure to hypoxia in transgenic mice expressing RNF213 R4757K in endothelial cells. a Several lines of transgenic or knockout or wild-type mice were exposed to hypoxia for 2 weeks at 8 % oxygen. Cerebral angiogenesis was evaluated by immunostaining Glut4. b Adaptive cerebral angiogenesis was abolished in transgenic mice overexpressing RNF213 R4757K (Human allelic ortholog of R4810K) in ECs, while in other mice adaptive angiogenesis was observed. Cited from Kobayashi et al. [21]

Fig. 5

Three-route model of the hypothetical molecular pathology of moyamoya disease/syndrome. The model assumes that any of three independent abnormalities, endothelial dysfunction, smooth muscle cell dysfunction, and abnormal hemostasis, can lead to exaggerated proliferation of SMCs. Each abnormality can result in vascular stenosis. RNF213 R4810K is the major detrimental factor that elicits endothelial cell dysfunction. Pro-inflammatory signals such as IFNs can activate the transcription of RNF213