A FBN1 3 ' UTR mutation variant is associated with endoplasmic reticulum stress in aortic aneurysm in Marfan syndrome
Por:
Siegert, AM, Diaz-Barriga, GG, Esteve-Codina, A, Navas-Madronal, M, del Blanco, DG, Alberch, J, Heath, S, Galan, M, Egea, G
Publicada:
1 ene 2019
Resumen:
Marfan syndrome (MFS) is caused by mutations in the protein fibrillin-1 (FBN1) which affects the integrity of connective tissue elastic fibres. The most severe clinical outcome is the formation of ascending aortic aneurysms. FBN1 mutations are extremely variable and the prediction of disease phenotype and aortic risk is challenging under the prevailing mutation type classification. Finding a better correlation between mutation type and disease development is crucial for patient treatment. By mRNA sequencing of cultured vascular smooth muscle cells derived from control subjects and from the dilated and non-dilated aortic tunica media of MFS patients, we found a scarcely described FBN1 3'UTR mutation. This mutation was accompanied by a clear gene ontological endoplasmic reticulum (ER) stress response in the non-dilated aortic zone, which was confirmed by the increased transcriptional expression of MANF, HSPA5, SEL1L, DDIT3/CHOP and CRELD2 as well as protein expression levels of BiP/GRP78, CHOP and sXBP1. Moreover, the ER stress response was accompanied by a decrease in the phosphorylation levels of the protein translation regulator elF2 alpha. In conclusion, we here identify a 3'UTR mutation of FBN1 in MFS patients, whose molecular mechanism suggest the involvement of the ER stress response in the formation of the aortic aneurysm. Our results emphasise the importance of mutations in non-coding regions and their resulting molecular mechanisms in the development of connective tissue diseases with impact on the cardiovascular system.
Filiaciones:
Siegert, AM:
Univ Barcelona, Sch Med & Hlth Sci, Dept Biomed Sci, C Casanova 143, E-08036 Barcelona, Spain
Diaz-Barriga, GG:
Univ Barcelona, Sch Med & Hlth Sci, Dept Biomed Sci, C Casanova 143, E-08036 Barcelona, Spain
Inst Biomed Invest August Pi & Sunyer IDIBAPS, Barcelona 08036, Spain
Univ Barcelona, Inst Neurosci, UBNeuro, E-08036 Barcelona, Spain
Inst Carlos III, Ctr Networked Biomed Res CIBERNED, Madrid 28031, Spain
Esteve-Codina, A:
BIST, Ctr Genom Regulat CRG, CNAG CRG, Barcelona 08028, Spain
Pompeu Fabra Univ, Barcelona 08002, Spain
Navas-Madronal, M:
St Pau Biomed Res Inst IIB St Pau, Barcelona 08025, Spain
ISCIII, CIBER Cardiovasc Dis CIBERCV, Madrid 28029, Spain
del Blanco, DG:
Univ Barcelona, Sch Med & Hlth Sci, Dept Biomed Sci, C Casanova 143, E-08036 Barcelona, Spain
Inst Biomed Invest August Pi & Sunyer IDIBAPS, Barcelona 08036, Spain
Alberch, J:
Univ Barcelona, Sch Med & Hlth Sci, Dept Biomed Sci, C Casanova 143, E-08036 Barcelona, Spain
Inst Biomed Invest August Pi & Sunyer IDIBAPS, Barcelona 08036, Spain
Univ Barcelona, Inst Neurosci, UBNeuro, E-08036 Barcelona, Spain
Inst Carlos III, Ctr Networked Biomed Res CIBERNED, Madrid 28031, Spain
Heath, S:
BIST, Ctr Genom Regulat CRG, CNAG CRG, Barcelona 08028, Spain
Pompeu Fabra Univ, Barcelona 08002, Spain
Galan, M:
St Pau Biomed Res Inst IIB St Pau, Barcelona 08025, Spain
ISCIII, CIBER Cardiovasc Dis CIBERCV, Madrid 28029, Spain
Egea, G:
Univ Barcelona, Sch Med & Hlth Sci, Dept Biomed Sci, C Casanova 143, E-08036 Barcelona, Spain
Inst Biomed Invest August Pi & Sunyer IDIBAPS, Barcelona 08036, Spain
Univ Barcelona, Inst Nanosci & Nanotechnol IN2UB, E-08036 Barcelona, Spain
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