Researchers in the laboratory of Eric Chien-Wei Liao, MD, PhD, and the Center for Craniofacial Innovation at Children’s Hospital of Philadelphia (CHOP) showed that three proteins play critical roles in the formation of orofacial clefts (OFCs). The three proteins are epithelial splicing regulatory proteins (ESRP1 and ESRP2) and catenin delta 1 (CTNND1). These findings provide new insights into OFC and can help guide the development of better genetic diagnostics for craniofacial conditions.
OFC represents one of the most common congenital conditions, and it can result from a combination of environmental and genetic factors. Recent genetic studies have shown that proteins ESRP1 and ESRP2 play a key role in the development of the face and that some versions of ESRP1/2, known as variants, can lead to OFC in humans. Gene variants arise when changes occur within a gene’s sequence, and these changes result in impaired gene function and disease. Computer tools can help predict disease-causing gene variants. However, functional testing of these variants in the laboratory is required to confirm the variant’s effect in the real world.
The Liao Lab gathered multiple ESRP1/2 variants that computers predicted to cause disease and tested their function in two model systems: (1) a zebrafish model that parallels many of the features in human facial development, and (2) a cell model that models human facial tissue. Liao Lab researchers found that many of the variants predicted to cause disease actually showed normal function in these model systems. The team also observed that ESRP1 affects the catenin delta 1 (CTNND1) gene, which is important for organizing cells in tissue such as in the face. Further, the team found that ESRP1 and CTNND1 appear together in embryonic and oral tissue. Liao Lab researchers created zebrafish that lacked ESRP1/2 and had craniofacial anomalies and found that overexpressing the CTNND1 gene helped restore some facial structures. Based on the fact that ESRP1 and CTNND1 were observed together in facial tissues, the team hypothesized that CTNND1 plays a significant role in OFC and excitingly discovered 13 new CTNND1 variants from genetic sequencing of OFC patients.
This study highlights the importance of functional testing for gene variants and the need for ESRP1/2 and CTNND1 acting together to regulate the formation of the face. The research team plans to continue investigating the roles of CTNND1 variants in OFC, which will further our understanding of OFC.
Read the full study published in Communications Biology.
Funding was provided by the National Institutes of Health (HG013031, DE932332, DE027983), Shriners Hospital for Children, and institutional support from Children’s Hospital of Philadelphia.
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Researchers in the laboratory of Eric Chien-Wei Liao, MD, PhD, and the Center for Craniofacial Innovation at Children’s Hospital of Philadelphia (CHOP) showed that three proteins play critical roles in the formation of orofacial clefts (OFCs). The three proteins are epithelial splicing regulatory proteins (ESRP1 and ESRP2) and catenin delta 1 (CTNND1). These findings provide new insights into OFC and can help guide the development of better genetic diagnostics for craniofacial conditions.
OFC represents one of the most common congenital conditions, and it can result from a combination of environmental and genetic factors. Recent genetic studies have shown that proteins ESRP1 and ESRP2 play a key role in the development of the face and that some versions of ESRP1/2, known as variants, can lead to OFC in humans. Gene variants arise when changes occur within a gene’s sequence, and these changes result in impaired gene function and disease. Computer tools can help predict disease-causing gene variants. However, functional testing of these variants in the laboratory is required to confirm the variant’s effect in the real world.
The Liao Lab gathered multiple ESRP1/2 variants that computers predicted to cause disease and tested their function in two model systems: (1) a zebrafish model that parallels many of the features in human facial development, and (2) a cell model that models human facial tissue. Liao Lab researchers found that many of the variants predicted to cause disease actually showed normal function in these model systems. The team also observed that ESRP1 affects the catenin delta 1 (CTNND1) gene, which is important for organizing cells in tissue such as in the face. Further, the team found that ESRP1 and CTNND1 appear together in embryonic and oral tissue. Liao Lab researchers created zebrafish that lacked ESRP1/2 and had craniofacial anomalies and found that overexpressing the CTNND1 gene helped restore some facial structures. Based on the fact that ESRP1 and CTNND1 were observed together in facial tissues, the team hypothesized that CTNND1 plays a significant role in OFC and excitingly discovered 13 new CTNND1 variants from genetic sequencing of OFC patients.
This study highlights the importance of functional testing for gene variants and the need for ESRP1/2 and CTNND1 acting together to regulate the formation of the face. The research team plans to continue investigating the roles of CTNND1 variants in OFC, which will further our understanding of OFC.
Read the full study published in Communications Biology.
Funding was provided by the National Institutes of Health (HG013031, DE932332, DE027983), Shriners Hospital for Children, and institutional support from Children’s Hospital of Philadelphia.
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