Extracellular Matrix Disorganization Caused by ADAMTS16 Deficiency Leads to Bicuspid Aortic Valve With Raphe...

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Genetics

Background:

• Understanding the molecular mechanisms of aortic valve development and bicuspid aortic valve (BAV) formation is crucial for optimizing BAV treatment strategies.
• The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family plays a role in cardiovascular development and diseases.
• Previous research has increasingly recognized genes involved in aortic valve development and BAV formation.

Purpose of the Study:

• To investigate the roles of ADAMTS family members in aortic valve development and BAV formation.
• To identify specific ADAMTS genes implicated in BAV etiology.
• To elucidate the molecular mechanisms underlying ADAMTS-associated BAV.

Main Methods:

• Screening of ADAMTS family genes in zebrafish and DNA sequencing in a BAV patient cohort.
• Gene expression analysis using in situ hybridization and genetic tracing in zebrafish and mouse models.
• Generation of ADAMTS gene knockout and knockin mouse models using CRISPR/Cas9.
• Lineage tracing, bulk RNA sequencing, and inducible pluripotent stem cell studies to analyze cellular regulation and signaling pathways.
• Immunohistochemistry to assess cardiac valve anomalies and extracellular matrix components.

Main Results:

• ADAMTS16 was identified as a BAV-causing gene, with a specific variant (p. H357Q) found in an inherited BAV family.
• ADAMTS16 exhibits a unique spatiotemporal expression pattern during aortic valve development.
• Adamts16-deficient mouse models displayed a BAV phenotype characterized by cusp fusion and valve thickening.
• ADAMTS16 deficiency in Tie2 lineage cells recapitulated the BAV phenotype, affecting endothelial and second heart field cells.
• Enhanced FAK signaling and elevated fibronectin levels were observed in ADAMTS16-deficient models.

Conclusions:

• A novel BAV-causing ADAMTS16 variant (p. H357Q) was identified.
• ADAMTS16 deficiency is directly linked to the formation of bicuspid aortic valves.
• These findings provide critical insights into the genetic and molecular basis of BAV.