PUBLICATION
Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations
- Authors
- Hong, T., Xiao, X., Ren, J., Cui, B., Zong, Y., Zou, J., Kou, Z., Jiang, N., Meng, G., Zeng, G., Shan, Y., Wu, H., Chen, Z., Liang, J., Xiao, X., Tang, J., Wei, Y., Ye, M., Sun, L., Li, G., Hu, P., Hui, R., Zhang, H., Wang, Y.
- ID
- ZDB-PUB-210319-6
- Date
- 2021
- Source
- Brain : a journal of neurology 144(9): 2648-2658 (Journal)
- Registered Authors
- Keywords
- MAP3K3, PIK3CA, cavernous malformations, haemorrhage, somatic mutation
- MeSH Terms
-
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Animals
- Child
- Child, Preschool
- Class I Phosphatidylinositol 3-Kinases/genetics*
- Female
- Hemangioma, Cavernous, Central Nervous System/diagnostic imaging*
- Hemangioma, Cavernous, Central Nervous System/genetics*
- Humans
- MAP Kinase Kinase Kinase 3/genetics*
- Male
- Middle Aged
- Mutation/genetics*
- Spinal Cord/diagnostic imaging*
- Young Adult
- Zebrafish
- PubMed
- 33729480 Full text @ Brain
Citation
Hong, T., Xiao, X., Ren, J., Cui, B., Zong, Y., Zou, J., Kou, Z., Jiang, N., Meng, G., Zeng, G., Shan, Y., Wu, H., Chen, Z., Liang, J., Xiao, X., Tang, J., Wei, Y., Ye, M., Sun, L., Li, G., Hu, P., Hui, R., Zhang, H., Wang, Y. (2021) Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations. Brain : a journal of neurology. 144(9):2648-2658.
Abstract
Cavernous malformations (CMs) affecting the central nervous system occur in approximately 0.16% to 0.4% of the general population. The majority (85%) of the CMs are in a sporadic form, but the genetic background of sporadic CMs remains enigmatic. Of the 81 patients, 73 (90.1%) patients were detected carrying somatic missense variants in 2 genes: MAP3K3 and PIK3CA by whole-exome sequencing (WES). The mutation spectrum correlated with lesion size (P = 0.001), anatomical distribution (P < 0.001), MRI appearance (P = 0.004) and haemorrhage events (P = 0.006). PIK3CA mutation was a significant predictor of overt haemorrhage events (P = 0.003, OR = 11.252, 95% CI = 2.275-55.648). Enrichment of endothelial cell (EC) population was associated with a higher fractional abundance of the somatic mutations. Overexpression of the MAP3K3 mutation perturbed angiogenesis of EC models in vitro and zebrafish embryos in vivo. Distinct transcriptional signatures between different genetic subgroups of sporadic CMs were identified by single-cell RNA-sequencing (scRNA-seq) and verified by pathological staining. Significant apoptosis in MAP3K3 mutation carriers and overexpression of GDF15 and SERPINA5 in PIK3CA mutation carriers contributed to their phenotype. We identified activating MAP3K3 and PIK3CA somatic mutations in the majority (90.1%) of sporadic CMs and PIK3CA mutations could confer a higher risk for overt haemorrhage. Our data provide insights into genomic landscapes, propose a mechanistic explanation and underscore the possibility of a molecular classification for sporadic CMs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping