Analysis of clinical and genetic characteristics in three cases of early-onset Moyamoya disease associated with ring finger protein 213 gene variants in infancy
10.3969/j.issn.1672-5921.2025.07.005
- VernacularTitle:环指蛋白213基因变异相关婴儿期早发型烟雾病三例临床及遗传学特征分析
- Author:
Yuan FENG
1
;
Xiaolong DENG
1
Author Information
1. 430015 华中科技大学同济医学院附属武汉儿童医院(武汉市妇幼保健院)小儿神经内科
- Publication Type:Journal Article
- Keywords:
Moyamoya disease;
Infant;
Ring finger protein 213 gene;
Clinical phenotype
- From:
Chinese Journal of Cerebrovascular Diseases
2025;22(7):487-496,505
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the clinical and genetic characteristics of infantile early-onset Moyamoya disease associated with ring finger protein 213(RNF213)gene variants.Methods This study included retrospective,consecutive case series of infantile early-onset Moyamoya disease admitted to the Department of Pediatric Neurology,Wuhan Children's Hospital,Tongji Medical College,Huazhong University of Science and Technology,between June 2020 and June 2024.General and clinical data were collected,including sex,age,chief complaint,admission time,history of present illness,personal history,family history,neurological physical examination,auxiliary investigations,diagnosis/treatment course,and follow-up status.Genetic testing results of the patients and their parents were analyzed.Mutation sites were screened and annotated through bioinformatics analysis,and suspicious variants were validated by Sanger sequencing.The molecular evolutionary genetics analysis software MEGA(v11.0)was used for amino acid sequence alignment and conservation analysis of identified missense mutations.Based on the protein structure databases,the three-dimensional structure of the missense proteins was obtained through cryo-electron microscopy.The identified missense mutations were mapped onto this structure,and PyMOL(v2.0.6)was used for protein structure visualization and hydrogen bond analysis at variant sites.Results(1)Three infants with early-onset Moyamoya disease were enrolled(1 male,2 females).Initial symptoms included epileptic seizures,transient ischemic attacks,or acute cerebral infarction.Genetic testing revealed RNF213 missense mutations in all three patients:patient 1 carried p.Arg4810Lys and p.Thr1727Met(both maternally inherited);patient 2 carried p.Arg4810Lys(paternally inherited);patient 3 carried a de novo p.Lys4136Gln mutation(both parents were wild-type).All patients underwent indirect cerebral revascularization.Postoperatively,epileptic seizures and cerebral ischemic events gradually resolved,the modified Rankin scale scores at the last follow-up were 2,1,and 2,respectively.(2)The amino acid residues threonine 1727(THR1727),lysine 4136(LYS4136),and arginine 4810(ARG4810)in the RNF213 protein were absolutely conserved across all three patients.Compared to wild-type ARG4810,the p.Arg4810Lys mutation occurred within an α-helix and reduced internal hydrogen bond interactions by one.The p.Thr1727Met mutation reduced hydrogen bonding by one compared to wild-type THR1727.The p.Lys4136Gln mutation reduced hydrogen bonding by one relative to wild-type LYS4136 and altered residues connecting two α-helices.Conclusions Infantile early-onset Moyamoya disease has insidious onset,severe progression,and diverse clinical manifestations,making it prone to misdiagnosis.RNF213 gene p.Arg4810Lys,p.Thr1727Met and p.Lys4136Gln mutations contribute to the pathogenesis of Moyamoya disease by affecting molecular mechanisms underlying its protein function.Early genetic testing for RNF213 variants aids clinical diagnosis.Indirect cerebral revascularization may benefit the affected infants.These findings require further validation through large-scale,prospective,multicenter studies.
