The Heart Valve Society

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Phenotyping of the First and Unique Knock-In Animal Model for Mitral Valve Prolapse: the FLNA-P637Q KI Rat
Romain Capoulade, Solena Le Scouarnec, Benjamin Lauzier, Simon Lecointe, Joelle Veziers, Richard Redon, Thierry Le Tourneau, Jean-Jacques Schott, Jean Mérot.
l'institut du thorax, Nantes, France.

OBJECTIVE: Mitral valve prolapse (MVP) is a frequent and morbid cardiovascular disease. Advances in genetics allowed the identification of the first causal gene in a large MVP family: three mutations of the FLNA gene coding for the Filamin A (FlnA) have been described. Recent comprehensive phenotyping of FLNA individuals also described a particular and unique expression of the disease, defined as a new type of mitral valve (MV) dystrophy/MVP. To date, only knock-out models were tested with varied results but we recently developed the first and unique knock-in (KI) rat model for the FLNA-P367Q mutation. The aim of this study was to perform a comprehensive phenotyping of this model.
METHODS: Using CRISPR-Cas9 technology, we developed a unique KI rat model for this FLNA-P637Q mutation. The phenotyping of the KI and wild-type (WT) rats was performed at 3, 6 and 13 weeks based on complementary approaches, such as standard histology, micro-CT scan and echocardiography.
RESULTS: Preliminary results established the presence of dystrophic MV. The histological analysis confirmed the MV leaflets were significantly thicker in the KI rats. Using micro CT and the complete 3D reconstruction of explanted heart, we showed that the volume of the MV leaflets were significantly higher in the KI vs WT rats. Echocardiographic evaluation also attested the presence of a dystrophic MV, and more interestingly that the valve function of KI rats mimicked the one of the human FLNA carriers.
CONCLUSIONS: This preliminary analysis of a unique KI rat model validates the presence of MVP/MV dystrophy, with an expression of the disease close to the one observed in human. This finding opens new avenue for the identification of new mechanisms involved in the development and/or progression of the disease, as well as the unique opportunity to identify therapeutic target for MVP.


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