PUBLICATION
Compound inheritance of EHHADH and MASP1 mutations contributes to nonsyndromic cleft lip: familial analysis and zebrafish models
- Authors
- Swatowska, P., Odrzywolski, A., Kuźniarz, K., Tylzanowski, P.
- ID
- ZDB-PUB-251211-17
- Date
- 2025
- Source
- Biology Open 14: (Journal)
- Registered Authors
- Keywords
- EHHADH, MASP1, Cartilage development, Cleft lip, Compound inheritance, Craniofacial development, Nonsyndromic, Zebrafish
- MeSH Terms
-
- Animals
- Cleft Lip*/diagnosis
- Cleft Lip*/genetics
- Disease Models, Animal
- Female
- Genetic Predisposition to Disease*
- Humans
- Male
- Mannose-Binding Protein-Associated Serine Proteases*/genetics
- Mutation*
- Pedigree
- Phenotype
- Zebrafish/genetics
- PubMed
- 41378467 Full text @ Biol. Open
Citation
Swatowska, P., Odrzywolski, A., Kuźniarz, K., Tylzanowski, P. (2025) Compound inheritance of EHHADH and MASP1 mutations contributes to nonsyndromic cleft lip: familial analysis and zebrafish models. Biology Open. 14:.
Abstract
Cleft lip with or without cleft palate (CL/P) represents one of the most common congenital craniofacial anomalies. Its complex genetic etiology remains incompletely understood. This study investigated compound inheritance of mutations in the EHHADH and MASP1 genes in a Polish family with three affected individuals using whole-genome sequencing and bioinformatic analysis, followed by zebrafish functional validation. We identified mutations in both genes that segregated with the CL/P phenotype. Network analysis demonstrated significant functional associations between these genes, with enrichment for innate immune response pathways. Using zebrafish models, we validated the phenotypic consequences of these mutations through mRNA injection experiments. Individual or combined injections of mutant EHHADH and MASP1 mRNAs resulted in craniofacial abnormalities, with co-injection producing the most severe phenotypes, including cleft formation. Alcian Blue staining revealed significant alterations in cartilage development, particularly in the ceratohyal angle and chondrocyte morphology. These changes may affect extracellular matrix composition and cartilage biomechanics, potentially disrupting the structural integrity and mechanical properties essential for proper craniofacial morphogenesis. Our findings suggest the possibility of a novel genetic mechanism for nonsyndromic CL/P involving the interaction between metabolic processes regulated by EHHADH and immune signaling pathways controlled by MASP1. This study expands our understanding of the genetic complexity underlying CL/P and highlights the potential intersection of immune regulation and metabolic processes in craniofacial development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping