Mutations of RNF213 are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish

Lin, J., Liang, J., Wen, J., Luo, M., Li, J., Sun, X., Xu, X., Li, J., Wang, D., Wang, J., Chen, H., Lai, R., Liang, F., Li, C., Ye, F., Zhang, J., Zeng, J., Yang, S., Sheng, W.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism   41(6): 1251-1263 (Journal)
Registered Authors
Yang, Shulan
RNF213 mutation, Sporadic cerebral cavernous malformation, mulberry-like cluster, rnf213a, zebrafish
MeSH Terms
  • Adenosine Triphosphatases/genetics*
  • Adult
  • Animals
  • Animals, Genetically Modified
  • Brain Neoplasms/genetics*
  • Child
  • Female
  • Hemangioma, Cavernous, Central Nervous System/genetics*
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Ubiquitin-Protein Ligases/genetics*
  • Zebrafish
  • Zebrafish Proteins/genetics*
32248732 Full text @ J. Cereb. Blood Flow Metab.
Although familial forms of cerebral cavernous malformation are mainly attributed to three CCM genes (KRIT1, CCM2 and PDCD10), no mutation is identified in sporadic cerebral cavernous malformation cases with a unique lesion, indicating additional genes for sporadic cerebral cavernous malformation. To screen the candidate genes, we conducted whole exome sequencing in 31 sporadic cerebral cavernous malformation patients and 32 healthy controls, and identified 5 affected individuals carrying 6 heterozygous deleterious mutations in RNF213 but no RNF213 mutation in healthy individuals. To further confirm RNF213 was associated with cerebral cavernous malformation, we generated rnf213a homozygous knockout zebrafish and found mutation of rnf213a in zebrafish led to a mulberry-like cluster of disordered-flow vascular channels which was reminiscent of human cerebral cavernous malformation. In addition, we revealed kbtbd7 and anxa6 were significantly downregulated due to rnf213a mutation through transcriptomic sequencing and RT-qPCR analysis. Based on the mulberry-like phenotype partly rescued by mRNA of kbtbd7 as well as anxa6, we suggested that rnf213a promoted mulberry-like cluster via downregulation of kbtbd7 and anxa6. Altogether, we firstly demonstrate RNF213is a novel candidate gene for sporadic cerebral cavernous malformation and the mutation of rnf213a is responsible for the mulberry-like cluster in zebrafish.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes