A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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-tekijät tai -toimittajat
Julkaisun tiedot
Julkaisun kaikki tekijät tai toimittajat: Haataja, Tatu J.K.; Capoulade, Romain; Lecointe, Simon; Hellman, Maarit; Merot, Jean; Permi, Perttu; Pentikäinen, Ulla
Lehti tai sarja: Biophysical Journal
ISSN: 0006-3495
eISSN: 1542-0086
Julkaisuvuosi: 2019
Volyymi: 117
Lehden numero: 8
Artikkelin sivunumerot: 1467-1475
Kustantaja: Elsevier (Cell Press); Biophysical Society
Julkaisumaa: Yhdysvallat (USA)
Julkaisun kieli: englanti
DOI: https://doi.org/10.1016/j.bpj.2019.08.032
Julkaisun avoin saatavuus: Ei avoin
Julkaisukanavan avoin saatavuus: Viivästetysti avoin julkaisukanava
Julkaisu on rinnakkaistallennettu (JYX): https://jyx.jyu.fi/handle/123456789/65929
Tiivistelmä
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.
YSO-asiasanat: synnynnäiset sydänviat; dysplasiat; hiippaläppä; geneettiset tekijät; mutaatiot; filamiinit
Vapaat asiasanat: critical structural defects; filamin A mutations; mitral valve dysplasia
Liittyvät organisaatiot
Hankkeet, joissa julkaisu on tehty
- Filamiinien fysiologisten ominaisuuksien
- Pentikäinen, Ulla
- Suomen Akatemia
- Laskostumattomien proteiinien konformationaalisten ominaisuuksien tutkiminen biofysikaalisin menetelmin
- Permi, Perttu
- Suomen Akatemia
OKM-raportointi: Kyllä
Raportointivuosi: 2019
JUFO-taso: 1