RNF213 Rare Variants in Slovakian and Czech Moyamoya Disease Patients

Area of Science:

• Genetics
• Neurology
• Vascular Biology

Background:

• Moyamoya disease is a cerebrovascular disorder characterized by occlusive lesions in the circle of Willis.
• RNF213/Mysterin is a known susceptibility gene for moyamoya disease, particularly the p.R4810K variant in East Asian populations.
• The role of non-founder RNF213 variants in Caucasian moyamoya disease patients remains under-investigated.

Purpose of the Study:

• To screen for and identify rare RNF213 variants in Slovakian and Czech moyamoya disease patients.
• To investigate the functional impact of identified RNF213 variants on endothelial cell function.
• To determine the contribution of RNF213 as a causative gene in a European Caucasian population.

Main Methods:

• Direct sequencing of 69 RNF213 coding exons in 18 moyamoya disease probands and one relative.
• Identification and characterization of novel and known RNF213 variants.
• In vitro functional assays using RNF213-transfected human umbilical vein endothelial cells to assess migration and tube formation.

Main Results:

• Four rare RNF213 variants (p.R4019C, p.E4042K, p.V4146A, p.W4677L) were identified in four patients, in addition to a previously reported variant (p.D4013N).
• One novel de novo mutation (p.V4146A) and two double mutations (p.R4019C, p.E4042K) were found.
• RNF213 variants p.D4013N, p.R4019C, and p.V4146A significantly reduced endothelial cell migration, while p.V4146A also impaired tube formation.

Conclusions:

• RNF213 rare variants were identified in 22.2% of Slovakian and Czech moyamoya disease patients.
• Identified variants, particularly p.V4146A, demonstrate disease-causing potential through impaired endothelial cell function.
• RNF213 is confirmed as a significant causative gene in a considerable proportion of Caucasian moyamoya disease patients.