Genetics and Biomarkers of Moyamoya Disease: Significance of RNF213 as a Susceptibility Gene

Abstract

Moyamoya disease is 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 still unknown, recent genome-wide and locus-specific association studies identified RNF213 as an important susceptibility gene of moyamoya disease among East Asian population. A polymorphism in c.14576G>A in RNF213 was identified in 95% of familial patients with moyamoya disease and 79% of sporadic cases, and patients having this polymorphism were found to have significantly earlier disease onset and a more severe form of moyamoya disease, such as the presentation of cerebral infarction and posterior cerebral artery stenosis. The exact mechanism by which the RNF213 abnormality relates to moyamoya disease remains unknown, while recent reports using genetically engineered mice lacking RNF213 by homologous recombination provide new insight for the pathogenesis of this rare entity. Regarding biomarkers of moyamoya disease, moyamoya disease is characterized by an increased expression of angiogenic factors and pro-inflammatory molecules such as vascular endothelial growth factors and matrix metalloproteinase-9, which may partly explain its clinical manifestations of the pathologic angiogenesis, spontaneous hemorrhage, and higher incidence of cerebral hyperperfusion after revascularization surgery. More recently, blockade of these pro-inflammatory molecules during perioperative period is attempted to reduce the potential risk of surgical complication including cerebral hyperperfusion syndrome. In this review article, we focus on the genetics and biomarkers of moyamoya disease, and sought to discuss their clinical implication.

Keywords: Biomarkers; Genetics; Moyamoya disease; RNF213; Susceptibility gene.

Figure 1

Gene construct of RNF213-deficient mice. Conventional knockout mice were generated by the Cre-lox system.

Figure 2

(A) Polymerase chain reaction (PCR) genotyping of wild-type mice (Wt.), homozygous RNF213- deficient mice (RNF213^-/-) and heterozygous RNF213- deficient mice (RNF213^-/+). (B, C) Microscopic view of the base of the brain at 16 weeks demonstrated no difference in the vascular structure of the circle of Willis between RNF213^-/- and Wt.

Figure 3

Photo-microscopic view of the wall of the common carotid artery (CCA) 14 days after CCA ligation (High-power, Elastica-Masson staining). Only Wt. exhibited temporary intimal hyperplasia and the medial layer after CCA ligation (Scale bar: 50 µm).

Figure 4

Demographic view of the possible mechanism underlying the development of moyamoya disease. IC-EC conversion: Internal carotid-external carotid conversion as a compensatory physiological reorganization system for moyamoya disease.

Figure 5

A 43-year old man with ischemic-onset moyamoya disease undergoing left superficial temporal artery-middle cerebral artery anastomosis. Postoperative single-photon emission computed tomography one day (A) and 14 days (B) after surgery demonstrating focal intense increase in cerebral blood flow at the site of the anastomosis (arrows).

Figure 6

Postoperative magnetic resonance (MR) angiography (A) and MR imaging of T2-wighted images (B) indicating patent bypass (arrow in A) and no evidence of vasogenic edema (B).