UCSF

The genes encoding extracellular matrix components and adhesion-related signaling molecules serve important roles in the heart, as evidenced by human genetic disorders affecting the aorta and aortic valve, such as Marfan, Williams, Loeys-Dietz, and Weill-Marchesani syndromes. Here, we identify new functions of the multiple EGF-like domain protein ITGBL1 given its human aortic expression and integrin sequence homology. Our results indicate ITGBL1 is a highly-conserved protein expressed in multiple species and homologous to the beta integrin stalk region. Altering Itgbl1 levels consistently affected zebrafish ventricular size while itgbl1 RNA introduction ameliorated the abnormality, suggesting a role of itgbl1 in zebrafish cardiac development. To identify potential molecular functions, human ITGBL1 expression and cell-based studies were performed. Expression data analysis for potential ITGBL1-associated pathways demonstrated significant enrichment for the extracellular matrix, adhesion and collagen functional processes. We found that cells engineered to express ITGBL1 demonstrate selective differential adhesion to collagens. Furthermore, collagen-dependent vascular endothelial cell network formation was inhibited by ITGBL1, independent of cell death. ITGBL1-expressing cells decreased SMAD reporter activity, suggesting ITGBL1 may influence the TGF-beta pathway and play role in extracellular matrix-dependent signaling. To evaluate the potential influence of ITGBL1 on human outflow tract abnormalities, we assessed genomic structural variation in individuals with hypoplastic left heart for 13q33.1 variation. We show that ITGBL1 is copy number variable in a hypoplastic left heart individual, and resulting truncation of the protein structure yields a continuing ITGBL1 function on adhesion verified in cells. These data support a fundamental role for the multiple EGF-like protein ITGBL1 in the heart. To our knowledge, these results are the first description of ITGBL1 potential roles in development.