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A Mutation in VWA1, Encoding von Willebrand Factor A Domain-Containing Protein 1, Is Associated With Hemifacial
Yibei Wang1,2, Lu Ping3, Xiaodong Luan4,5,6
1Department of Otolaryngology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Background:
Hemifacial microsomia (HFM) is a type of rare congenital syndrome caused by developmental disorders of the first and second pharyngeal arches that occurs in one out of 5,600 live births. There are significant gaps in our knowledge of the pathogenic genes underlying this syndrome.
Methods:
Whole exome sequencing (WES) was performed on five patients, one asymptomatic carrier, and two marry-in members of a five-generation pedigree. Structure of WARP (product of VWA1) was predicted using the Phyre2 web portal. In situ hybridization and vwa1-knockdown/knockout studies in zebrafish using morpholino and CRISPR/Cas9 techniques were performed. Cartilage staining and immunofluorescence were carried out.
Results:
Through WES and a set of filtration, we identified a c.G905A:p.R302Q point mutation in a novel candidate pathogenic gene, VWA1. The Phyre2 web portal predicted alterations in secondary and tertiary structures of WARP, indicating changes in its function as well. Predictions of protein-to-protein interactions in five pathways related to craniofacial development revealed possible interactions with four proteins in the FGF pathway. Knockdown/knockout studies of the zebrafish revealed deformities of pharyngeal cartilage. A decrease of the proliferation of cranial neural crest cells (CNCCs) and alteration of the structure of pharyngeal chondrocytes were observed in the morphants as well.
Conclusion:
Our data suggest that a mutation in VWA1 is functionally linked to HFM through suppression of CNCC proliferation and disruption of the organization of pharyngeal chondrocytes.
Insights
A mutation in the VWA1 gene is linked to hemifacial microsomia (HFM). This genetic change disrupts cranial neural crest cell proliferation and pharyngeal chondrocyte organization, offering new insights into HFM pathogenesis.
Area of Science:
- Genetics and Developmental Biology
- Craniofacial Development
- Rare Diseases
Background:
- Hemifacial microsomia (HFM) is a rare congenital disorder affecting first and second pharyngeal arch development, occurring in 1 in 5,600 live births.
- Significant knowledge gaps exist regarding the genetic basis of HFM.
Purpose of the Study:
- To identify novel pathogenic genes associated with Hemifacial Microsomia (HFM).
- To investigate the functional role of the VWA1 gene in craniofacial development.
Main Methods:
- Whole exome sequencing (WES) was employed on a five-generation pedigree.
- VWA1 gene function was assessed using zebrafish models (morpholino and CRISPR/Cas9) and in silico protein structure prediction.
- Craniofacial development pathways were analyzed, including cranial neural crest cell (CNCC) proliferation and pharyngeal chondrocyte organization.
Main Results:
- A novel point mutation (c.G905A:p.R302Q) in the VWA1 gene was identified as a candidate cause of HFM.
- VWA1 mutation predicted to alter WARP protein structure and function, with potential interactions in the FGF pathway.
- Zebrafish VWA1 knockdown/knockout resulted in pharyngeal cartilage deformities, reduced CNCC proliferation, and altered pharyngeal chondrocytes.
Conclusions:
- The study implicates VWA1 mutations in the etiology of Hemifacial Microsomia.
- VWA1's role in suppressing CNCC proliferation and organizing pharyngeal chondrocytes is crucial for normal craniofacial development.
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