PUBLICATION
Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis
- Authors
- Caetano da Silva, C., Macias Trevino, C., Mitchell, J., Murali, H., Tsimbal, C., Dalessandro, E., Carroll, S.H., Kochhar, S., Curtis, S.W., Cheng, C.H.E., Wang, F., Kutschera, E., Carstens, R.P., Xing, Y., Wang, K., Leslie, E.J., Liao, E.C.
- ID
- ZDB-PUB-240825-10
- Date
- 2024
- Source
- Communications biology 7: 10401040 (Journal)
- Registered Authors
- Dalessandro, Eileen, Liao, Eric
- Keywords
- none
- MeSH Terms
-
- Mutation
- Alternative Splicing
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Cleft Lip/genetics
- Cleft Palate*/embryology
- Cleft Palate*/genetics
- RNA-Binding Proteins*/genetics
- RNA-Binding Proteins*/metabolism
- Protein Isoforms*/genetics
- Protein Isoforms*/metabolism
- Humans
- Mice
- Cell Line
- Zebrafish*/embryology
- Zebrafish*/genetics
- Animals
- PubMed
- 39179789 Full text @ Commun Biol
Citation
Caetano da Silva, C., Macias Trevino, C., Mitchell, J., Murali, H., Tsimbal, C., Dalessandro, E., Carroll, S.H., Kochhar, S., Curtis, S.W., Cheng, C.H.E., Wang, F., Kutschera, E., Carstens, R.P., Xing, Y., Wang, K., Leslie, E.J., Liao, E.C. (2024) Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis. Communications biology. 7:10401040.
Abstract
Orofacial cleft (OFC) is a common human congenital anomaly. Epithelial-specific RNA splicing regulators ESRP1 and ESRP2 regulate craniofacial morphogenesis and their disruption result in OFC in zebrafish, mouse and humans. Using esrp1/2 mutant zebrafish and murine Py2T cell line models, we functionally tested the pathogenicity of human ESRP1/2 gene variants. We found that many variants predicted by in silico methods to be pathogenic were functionally benign. Esrp1 also regulates the alternative splicing of Ctnnd1 and these genes are co-expressed in the embryonic and oral epithelium. In fact, over-expression of ctnnd1 is sufficient to rescue morphogenesis of epithelial-derived structures in esrp1/2 zebrafish mutants. Additionally, we identified 13 CTNND1 variants from genome sequencing of OFC cohorts, confirming CTNND1 as a key gene in human OFC. This work highlights the importance of functional assessment of human gene variants and demonstrates the critical requirement of Esrp-Ctnnd1 acting in the embryonic epithelium to regulate palatogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping