Dataset Information

Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis.

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.

SUBMITTER: Caetano da Silva C

PROVIDER: S-EPMC11344038 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis.

Caetano da Silva Caroline C Macias Trevino Claudio C Mitchell Jason J Murali Hemma H Tsimbal Casey C Dalessandro Eileen E Carroll Shannon H SH Kochhar Simren S Curtis Sarah W SW Cheng Ching Hsun Eric CHE Wang Feng F Kutschera Eric E Carstens Russ P RP Xing Yi Y Wang Kai K Leslie Elizabeth J EJ Liao Eric C EC

Communications biology 20240823 1

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 ...[more]

PMID: 39179789

Similar Datasets

Project description:Orofacial clefts are among the most prevalent birth defects, with severe medical and psychosocial consequences. Cleft lip with or without cleft palate (CL ± P) and cleft palate only (CPO) affect on average nearly 1/700 births worldwide. The cause of most non-syndromic cases is unknown. Maternal factors and disorders are assumed to modify the risk of orofacial clefting. In the present study, we performed a systematic review and meta-analysis to analyze the effects of maternal underweight, obesity, hypertension, diabetes, as well as smoking, and alcohol consumption on the development of orofacial clefts. As CL ± CP and CPO have distinct pathogenetic backgrounds, these cleft subtypes were assessed separately. Altogether, 5,830 studies were identified and 64 of them met the inclusion and exclusion criteria. Obesity significantly elevated the odds of clefting (OR = 1.28, CI:1.08-1.51) (ORCL±CP = 1.23, CI:1.01-1.50; ORCPO = 1.31, CI:0.97-1.77). Maternal underweight also significantly increased the odds of clefting (OR = 1.21 CI:1.06-1.38). In mothers with type 1 diabetes, the odds of cleft development were significantly elevated (OR = 1,75, CI:1.45-2.12). Essential hypertension was also associated with higher odds of developing cleft (OR = 1.55, CI:1.18-2.03). Smoking during pregnancy significantly elevated the odds of cleft development (OR = 1.55, CI:1.34-1.79) (ORCL±CP = 1.58, CI:1.36-1.83; ORCPO = 1.50, CI:1.15-1.96). Passive smoking was even more damaging than active tobacco use, but alcohol consumption had no effect. In conclusion, this study clearly showed the importance of maintaining normal maternal body weight and emphasized the importance of hypertension and type 1 diabetes care in the first months of pregnancy. It also highlighted similarnegative effects of passive and active smoking, while alcohol consumption did not seem to be a significant risk factor for cleft development. However, there is a complete lack of available studies on the interactions of these factors, which is an essential direction for improving prevention.

Dataset Information

Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis.

Publications

Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets