Deletion of Fstl1 (Follistatin-Like 1) From the Endocardial/Endothelial Lineage Causes Mitral Valve Disease

Abstract

We report on a mouse model in which deletion of Fstl1 from the endocardial/endothelial lineage results in deformed mitral valves, which cause regurgitation, heart failure, and early cardiac death. The findings provide a potential molecular target for the clinical research into myxomatous mitral valve disease.

Structural and functional study of FK domain of Fstl1

“…Fstl1 is a TGF‐β superfamily binding protein and has been identified as a bone morphogenetic protein 4 (BMP4) antagonist controlling embryonic development . Fstl1 is also involved in many pathological processes, including carcinogenesis and metastasis, inflammatory and autoimmune diseases, cardiovascular diseases, and organ fibrosis . Despite extensive studies for Fstl1 have been performed, no structural information is available for this important molecule.…”

“…1 Fstl1 is also involved in many pathological processes, including carcinogenesis and metastasis, inflammatory and autoimmune diseases, cardiovascular diseases, and organ fibrosis. 16,[31][32][33][34] Despite extensive studies for Fstl1 have been performed, no structural information is available for this important molecule. In our report, we solved the high-resolution crystal structure of FK domain of Fstl1, analyzed its unique characteristics, Immunoblotting was performed to detect the protein levels of α-SMA and β-actin (n = 4 per group), three repetitive experiments were shown for each group and investigated its contribution to the function of full-length Fstl1.…”

Identifying pathogenic variants in the Follistatin‐like 1 gene (FSTL1) in patients with skeletal and atrioventricular valve disorders

“…We have recently prepared a global and conditional knockout of Follistatin‐like 1 ( Fstl1 ) (Prakash et al, ; Sylva et al, ) which both show congenital abnormalities (see below). FSTL1 is a secreted glycoprotein (OMIM 605547), belonging to SPARC family of proteins (Sylva, Moorman, & Hoff, ), and is a potential prognostic marker for cardiovascular disease (Widera et al, ).…”

“…Cardiomyocyte‐specific deletion of Fstl1 using αMHC‐Cre (Shimano et al, ) or fibroblasts specific deletion using S100A4‐Cre (Tanaka et al, ) resulted in viable offspring with no reported developmental defects. However, conditional ablation of Fstl1 from the endocardial/endothelial lineage using Tie2‐Cre ( Fstl1 endoKO) results in neonatal lethality between 2 and 4 weeks after birth (Prakash et al, ). These Fstl1 endoKO mice showed profound cardiac and valve defects, including an enlarged stressed heart and long and thick atrioventricular valves, displaying a myxomatous phenotype and being dysfunctional (Prakash et al, ).…”

“…However, conditional ablation of Fstl1 from the endocardial/endothelial lineage using Tie2‐Cre ( Fstl1 endoKO) results in neonatal lethality between 2 and 4 weeks after birth (Prakash et al, ). These Fstl1 endoKO mice showed profound cardiac and valve defects, including an enlarged stressed heart and long and thick atrioventricular valves, displaying a myxomatous phenotype and being dysfunctional (Prakash et al, ). The Fstl1 endoKO mice also have cardiac conduction abnormalities including fragmented QRS and increased QT intervals.…”