Abstract
Mitral valve prolapse (MVP) is a common cardiac valve disease that often progresses to serious secondary complications requiring surgery. MVP manifests as extracellular matrix disorganization and biomechanically incompetent tissues in the adult setting. However, MVP has recently been shown to have a developmental basis, as multiple causal genes expressed during embryonic development have been identified. Disease phenotypes have been observed in mouse models with human MVP mutations as early as birth. This study focuses on the developmental function of DCHS1, one of the first genes to be shown as causal in multiple families with non-syndromic MVP. By using various biochemical techniques as well as mouse and cell culture models, we demonstrate a unique link between DCHS1-based cell adhesions and the septin-actin cytoskeleton through interactions with cytoplasmic protein Lix1-Like (LIX1L). This DCHS1-LIX1L-SEPT9 axis interacts with and promotes filamentous actin organization to direct cell-ECM alignment and valve tissue shape.
Highlights
Mitral Valve Prolapse (MVP) is one of the most common forms of cardiac valve disease, affecting ~2–3% of the human population
This study focuses on a previously identified MVP causal gene, Dachsous Cadherin Related-1 (DCHS1) [3], with an aim to establish intracellular pathways mediated by this large, atypical cadherin protein
To elucidate novel protein interactors of DCHS1 beyond the well-known FAT4 binding partner, a yeast two-hybrid (Y2H) screen was performed using the cytoplasmic portion of DCHS1 as bait
Summary
Mitral Valve Prolapse (MVP) is one of the most common forms of cardiac valve disease, affecting ~2–3% of the human population. 1 in 10 MVP patients will require surgery for valve repair or replacement, and it is currently the fastest growing cardiovascular intervention in the Western world [1,2]. MVP is characterized by disrupted extracellular matrix (ECM) resulting in biomechanically incompetent mitral valve leaflets that are no longer able to close during ventricular systole. Progression of MVP can lead to serious secondary complications such as arrythmias, heart failure and sudden cardiac death. This study focuses on a previously identified MVP causal gene, DCHS1 [3], with an aim to establish intracellular pathways mediated by this large, atypical cadherin protein
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