PUBLICATION
Novel Mutation of LRP6 Identified in Chinese Han Population Links Canonical WNT Signaling to Neural Tube Defects
- Authors
- Shi, Z., Yang, X., Li, B.B., Chen, S., Yang, L., Cheng, L., Zhang, T., Wang, H., Zheng, Y.
- ID
- ZDB-PUB-170930-4
- Date
- 2017
- Source
- Birth defects research 110(1): 63-71 (Journal)
- Registered Authors
- Keywords
- LRP6, PCP signaling, WNT/β-catenin signaling, mutation, neural tube defects
- MeSH Terms
-
- Animals
- Asian People/genetics
- Cell Polarity/genetics
- Child
- Child, Preschool
- China
- Ethnicity/genetics
- Female
- Gene Expression Regulation, Developmental
- Humans
- Infant
- Infant, Newborn
- Low Density Lipoprotein Receptor-Related Protein-6/genetics*
- Low Density Lipoprotein Receptor-Related Protein-6/metabolism
- Male
- Mutation/genetics
- Neural Tube/metabolism
- Neural Tube Defects/genetics*
- Neurulation/genetics
- Signal Transduction/genetics
- Wnt Proteins/genetics
- Wnt Signaling Pathway/genetics*
- Zebrafish/genetics
- PubMed
- 28960852 Full text @ Birth Defects Res
Citation
Shi, Z., Yang, X., Li, B.B., Chen, S., Yang, L., Cheng, L., Zhang, T., Wang, H., Zheng, Y. (2017) Novel Mutation of LRP6 Identified in Chinese Han Population Links Canonical WNT Signaling to Neural Tube Defects. Birth defects research. 110(1):63-71.
Abstract
Background Neural tube defects (NTDs), the second most frequent cause of human congenital abnormalities, are debilitating birth defects due to failure of neural tube closure. It has been shown that noncanonical WNT/planar cell polarity (PCP) signaling is required for convergent extension (CE), the initiation step of neural tube closure (NTC). But the effect of canonical WNT//β-catenin signaling during NTC is still elusive. LRP6 (low density lipoprotein receptor related proteins 6) was identified as a co-receptor for WNT/β-catenin signaling, but recent studies showed that it also can mediate WNT/PCP signaling.
Methods In this study, we screened mutations in the LRP6 gene in 343 NTDs and 215 ethnically matched normal controls of Chinese Han population.
Results Three rare missense mutations (c.1514A>G, p.Y505C); c.2984A>G, p.D995G; and c.4280C>A, p.P1427Q) of the LRP6 gene were identified in Chinese NTD patients. The Y505C mutation is a loss-of-function mutation on both WNT/β-catenin and PCP signaling. The D995G mutation only partially lost inhibition on PCP signaling without affecting WNT/β-catenin signaling. The P1427Q mutation dramatically increased WNT/β-catenin signaling but only mildly loss of inhibition on PCP signaling. All three mutations failed to rescue CE defects caused by lrp6 morpholino oligos knockdown in zebrafish. Of interest, when overexpressed, D995G did not induce any defects, but Y505C and P1427Q caused more severe CE defects in zebrafish.
Conclusion Our results suggested that over-active canonical WNT signaling induced by gain-of-function mutation in LRP6 could also contribute to human NTDs, and a balanced WNT/β-catenin and PCP signaling is probably required for proper neural tube development. Birth Defects Research, 2017.© 2017 Wiley Periodicals, Inc.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping