The PDGFRβ-E162K variant alters receptor function and induces valvular defects resembling myxomatous degeneration in a mouse model, establishing it as a causal driver of mitral valve prolapse.
Does the PDGFRβ-E162K variant contribute to the development of mitral valve abnormalities resembling myxomatous degeneration?
The PDGFRβ-E162K variant is a causal driver of myxomatous mitral valve degeneration, providing a new murine model for studying non-syndromic mitral valve prolapse.
Abstract Background Myxomatous degeneration leading to mitral valve prolapse (MVP) is the most common cause of mitral regurgitation. Although familial clustering is frequently observed, only a limited number of pathogenic genes have been identified. Recently, we identified a missense variant in platelet-derived growth factor receptor β (PDGFRβ-E162K) in a family affected by MVP. Purpose To determine whether the PDGFRβ E162K substitution contributes to the development of mitral valve abnormalities. Methods Functional effects of the variant were assessed in HeLa cells overexpressing wild-type (WT) or mutant PDGFRβ. Using CRISPR/Cas9, we generated a mouse model carrying the murine equivalent of the human variant (PDGFRβ-E161K). Adult mice underwent transthoracic echocardiography, and histological analyses were performed in adult and neonatal mice to identify valvular abnormalities. Additionally, adult hearts were cultured in the Miniature Tissue Culture System to evaluate the influence of altered mechanical stress. Results Cells expressing PDGFRβ-E162K displayed enhanced proliferation and reduced migration compared to WT cells. In addition, mutant cells showed reduced responsiveness to PDGF stimulation, altered PDGFRβ surface expression, and changes in downstream signaling via p38MAPK and ERK1. In vivo, PDGFRβ-E161K mutant mice (PDGFRβE161K/- and PDGFRβE161K/E161K) exhibited an enlarged mitral valve annulus. Homozygous mice showed thickening of the posterior leaflet free edge, accompanied by increased collagen I and versican B expression and endothelial detachment. These abnormalities were absent in neonatal mice at day 1. Ex vivo cultures showed an altered mitral valve morphology in PDGFRβE161K/- hearts compared with WT controls in response to changed hemodynamic conditions. Conclusions The PDGFRβ-E162K variant alters PDGFRβ function in a context-dependent manner and leads to valvular defects that resemble the myxomatous degeneration observed in MVP. The PDGFRβ-E161K mouse represents the first model of acquired non-syndromic mitral valve disease driven by a variant identified in MVP patients, establishing it as a valuable tool for future mechanistic and therapeutic studies. Screening for PDGFRβ variants may therefore be beneficial for families with MVP to support appropriate clinical follow-up and genetic counselling.
Ouraoui et al. (Fri,) conducted a other in Myxomatous mitral valve degeneration. PDGFRβ-E162K variant vs. Wild-type was evaluated on Valvular abnormalities. The PDGFRβ-E162K variant alters receptor function and induces valvular defects resembling myxomatous degeneration in a mouse model, establishing it as a causal driver of mitral valve prolapse.