Critical Structural Defects Explain Filamin A Mutations Causing Mitral Valve Dysplasia
Haataja, T. J., Capoulade, R., Lecointe, S., Hellman, M., Merot, J., Permi, P., & Pentikäinen, U. (2019). Critical Structural Defects Explain Filamin A Mutations Causing Mitral Valve Dysplasia. Biophysical Journal, 117(8), 1467-1475. https://doi.org/10.1016/j.bpj.2019.08.032
Published inBiophysical Journal
© 2019 Biophysical Society.
Mitral valve diseases affect approximately 3% of the population and are the most common reasons for valvular surgery because no drug-based treatments exist. Inheritable genetic mutations have now been established as the cause of mitral valve insufficiency, and four different missense mutations in the filamin A gene (FLNA) have been found in patients suffering from non-syndromic mitral valve dysplasia (MVD). The FLNA protein is expressed, in particular, in endocardial endothelia during fetal valve morphogenesis and is key in cardiac development. The FLNA-MVD causing mutations are clustered in the N-terminal region of FLNA. How the mutations in FLNA modify its structure and function, have mostly remained elusive. In this study, using NMR spectroscopy and interaction assays, we investigated FLNA-MVD causing V711D and H743P mutations. Our results clearly indicated that both mutations almost completely destroy the folding of the FLNA5 domain, where the mutation is located, and also affect the folding of the neighboring FLNA4 domain. The structure of the neighboring FLNA6 domain was not affected by the mutations. These mutations also completely abolish FLNA’s interactions with protein tyrosine phosphatase (PTP) non-receptor type 12 (PTPN12), which has been suggested to contribute to the pathogenesis of FLNA-MVD. Taken together, our results provide an essential structural and molecular framework for understanding the molecular bases of FLNA-MVD, which is crucial for the development of new therapies to replace surgery. ...
PublisherElsevier (Cell Press); Biophysical Society
Publication in research information system
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Related funder(s)Academy of Finland
Funding program(s)Research costs of Academy Research Fellow, AoF; Academy Project, AoF
Additional information about fundingThis work was supported by Academy of Finland [283481 to U.P, and 288235 to P.P] and the Fédération Française de Cardiologie (2011, Paris, France to J.M) and Inserm Translational Research Grant (2012-2016, Paris, France). Dr. R Capoulade is supported by a grant from Institut de France - Fondation Lefoulon-Delalande (Paris, France) and a “Connect Talent” research chair from Region Pays de la Loire and Nantes Metropole (France). ...
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