Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis
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.
Authors
- Caroline Caetano da Silva (ORCID: https://orcid.org/0000-0001-9044-7348)
- Eric Kutschera (ORCID: https://orcid.org/0000-0002-2160-1820)
- Feng Wang (ORCID: https://orcid.org/0000-0001-8346-4692)
- Shannon H. Carroll (ORCID: https://orcid.org/0009-0008-8577-9012)
- Hemma Murali (ORCID: https://orcid.org/0000-0001-6896-1156)
- Russ P. Carstens (ORCID: https://orcid.org/0000-0002-8083-0412)
- Claudio Macias-Treviño (ORCID: https://orcid.org/0000-0002-3276-2064)
- Sarah W. Curtis (ORCID: https://orcid.org/0000-0002-9131-9601)
- Casey Tsimbal
- Eric C. Liao (ORCID: https://orcid.org/0000-0001-6385-7448)
- Elizabeth J. Leslie (ORCID: https://orcid.org/0000-0002-5735-1712)
- Yi Xing (ORCID: https://orcid.org/0000-0001-9257-7613)
- Kai Wang (ORCID: https://orcid.org/0000-0002-5585-982X)
- Ching Hsun Eric Cheng
- Jason W. Mitchell (ORCID: https://orcid.org/0000-0002-0840-9404)
- Simren Kochhar
- Eileen Dalessandro
Institutions
- Children's Hospital of Philadelphia (US)
- Harvard University (US)
- Emory University (US)
- Massachusetts General Hospital (US)
- Shriners Hospitals for Children - Tampa (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-08-23
- DOI
- https://doi.org/10.1038/s42003-024-06715-3
- Citations
- 10
- Primary Topic
- Cleft Lip and Palate Research
- Type
- article
- Field-Weighted Citation Impact
- 5.50
Funders
- Massachusetts General Hospital
- Children's Hospital of Philadelphia
- Shriners Hospitals for Children
- National Institutes of Health
- Intellectual and Developmental Disabilities Research Center