PUBLICATION
DVL mutations identified from human neural tube defects and Dandy-Walker malformation obstruct the Wnt signaling pathway
- Authors
- Liu, L., Liu, W., Shi, Y., Li, L., Gao, Y., Lei, Y., Finnell, R., Zhang, T., Zhang, F., Jin, L., Li, H., Tao, W., Wang, H.
- ID
- ZDB-PUB-200910-6
- Date
- 2020
- Source
- Journal of genetics and genomics = Yi chuan xue bao 47(6): 301-310 (Journal)
- Registered Authors
- Keywords
- DVL genes, Dandy-Walker malformation, Mutation, NTD, Wnt pathway
- MeSH Terms
-
- Aborted Fetus/pathology
- Animals
- Cell Polarity/genetics
- Dandy-Walker Syndrome/genetics*
- Dandy-Walker Syndrome/pathology
- Dishevelled Proteins/genetics*
- Gene Expression Regulation, Developmental/genetics
- Humans
- Mutation/genetics
- Neural Tube Defects/genetics*
- Neural Tube Defects/pathology
- Transcriptional Activation/genetics
- Wnt Signaling Pathway
- Zebrafish/genetics
- PubMed
- 32900645 Full text @ J. Genet. Genomics
Citation
Liu, L., Liu, W., Shi, Y., Li, L., Gao, Y., Lei, Y., Finnell, R., Zhang, T., Zhang, F., Jin, L., Li, H., Tao, W., Wang, H. (2020) DVL mutations identified from human neural tube defects and Dandy-Walker malformation obstruct the Wnt signaling pathway. Journal of genetics and genomics = Yi chuan xue bao. 47(6):301-310.
Abstract
Wnt signaling pathways, including the canonical Wnt/β-catenin pathway, planar cell polarity pathway, and Wnt/Ca2+ signaling pathway, play important roles in neural development during embryonic stages. The DVL genes encode the hub proteins for Wnt signaling pathways. The mutations in DVL2 and DVL3 were identified from patients with neural tube defects (NTDs), but their functions in the pathogenesis of human neural diseases remain elusive. Here, we sequenced the coding regions of three DVL genes in 176 stillborn or miscarried fetuses with NTDs or Dandy-Walker malformation (DWM) and 480 adult controls from a Han Chinese population. Four rare mutations were identified: DVL1 p.R558H, DVL1 p.R606C; DVL2 p.R633W, and DVL3 p.R222Q. To assess the effect of these mutations on NTDs and DWM, various functional analyses such as luciferase reporter assay, stress fiber formation, and in vivo teratogenic assay were performed. The results showed that the DVL2 p.R633W mutation destabilized DVL2 protein and upregulated activities for all three Wnt signalings (Wnt/β-catenin signaling, Wnt/planar cell polarity signaling, and Wnt/Ca2+ signaling) in mammalian cells. In contrast, DVL1 mutants (DVL1 p.R558H and DVL1 p.R606C) decreased canonical Wnt/β-catenin signaling but increased the activity of Wnt/Ca2+ signaling, and DVL3 p.R222Q only decreased the activity of Wnt/Ca2+ signaling. We also found that only the DVL2 p.R633W mutant displayed more severe teratogenicity in zebrafish embryos than wild-type DVL2. Our study demonstrates that these four rare DVL mutations, especially DVL2 p.R633W, may contribute to human neural diseases such as NTDs and DWM by obstructing Wnt signaling pathways.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping