A1 Journal article (refereed)
Critical Structural Defects Explain Filamin A Mutations Causing Mitral Valve Dysplasia (2019)
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
JYU authors or editors
Publication details
All authors or editors: Haataja, Tatu J.K.; Capoulade, Romain; Lecointe, Simon; Hellman, Maarit; Merot, Jean; Permi, Perttu; Pentikäinen, Ulla
Journal or series: Biophysical Journal
ISSN: 0006-3495
eISSN: 1542-0086
Publication year: 2019
Volume: 117
Issue number: 8
Pages range: 1467-1475
Publisher: Elsevier (Cell Press); Biophysical Society
Publication country: United States
Publication language: English
DOI: https://doi.org/10.1016/j.bpj.2019.08.032
Publication open access: Not open
Publication channel open access: Delayed open access channel
Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/65929
Abstract
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.
Keywords: congenital heart diseases; dysplasia; mitral valve; genetic factors; mutations; filamins
Free keywords: critical structural defects; filamin A mutations; mitral valve dysplasia
Contributing organizations
Related projects
- Filamiinien fysiologisten ominaisuuksien
- Pentikäinen, Ulla
- Research Council of Finland
- Conformational properties of intrinsically disordered proteins - biophysical characterization
- Permi, Perttu
- Research Council of Finland
Ministry reporting: Yes
Reporting Year: 2019
JUFO rating: 1