Peripheral bloodGATA2expression impactsRNF213mutation penetrance and clinical severity in moyamoya disease

Abstract

ABSTRACTBackgroundThe p.R4810K founder mutation in theRNF213gene confers susceptibility to moyamoya disease (MMD) and non-MMD intracranial artery disease. However, penetrance is incomplete, and the underlying molecular mechanism remains unknown.Methods and ResultsTranscriptome analysis of peripheral blood was conducted with 9 MMD patients and 5 unaffected mutation carriers from 4 familial MMD pedigrees. Bayesian network analysis identified upregulated gene modules associated with lipid metabolism and leukocyte development (includingGATA2andSLC45A3), and EGFR signaling (UBTD1). It also identified downregulated gene modules related to mitochondrial ribosomal proteins (RPS3AandRPL26), and cytotoxic T cell immunity (GZMAandTRGC1). TheGATA2network was replicated through WGCNA analysis and further examined in a case-control study, comprising 43 MMD patients, 16 non-MMD patients, 19 unaffected carriers, and 35 healthy controls.GATA2exhibited a significant linear correlation withSLC45A3and was significantly higher in MMD patients compared to age- and sex-matched unaffected carriers or wild-type controls. Among patients with the p.R4810K mutation, higherGATA2expression was associated with an earlier age of onset, bilateral involvement, and symptomatic disease onset.ConclusionsPeripheral bloodGATA2expression was associated with increased penetrance of theRNF213mutation and more severe clinical manifestations in MMD.