Genetic and functional implications of an exonic TRIM55 variant in heart failure

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)


Interna författare/redaktörer


Publikationens författare: Heliste J, Chheda H, Paatero I, Salminen TA, Akimov Y, Paavola J, Elenius K, Aittokallio T
Förläggare: Elsevier
Publiceringsår: 2019
Tidskrift: Journal of Molecular and Cellular Cardiology
Tidskriftsakronym: J Mol Cell Cardiol
Volym: 138
Artikelns första sida, sidnummer: 222
Artikelns sista sida, sidnummer: 233
ISSN: 1095-8584


Abstrakt

Background

To
tackle the missing heritability of sporadic heart failure, we screened
for novel heart failure-associated genetic variants in the Finnish
population and functionally characterized a novel variant in vitro and in vivo.

Methods and results

Heart
failure-associated variants were screened in genotyping array data of
the FINRISK study, consisting of 994 cases and 20,118 controls. Based on
logistic regression analysis, a potentially damaging variant in TRIM55
(rs138811034), encoding an E140K variant, was selected for validations.
In HL-1 cardiomyocytes, we used CRISPR/Cas9 technology to introduce the
variant in the endogenous locus, and additionally TRIM55 wildtype or
E140K was overexpressed from plasmid. Functional responses were profiled
using whole-genome RNA sequencing, RT-PCR and Western analyses, cell
viability and cell cycle assays and cell surface area measurements. In
zebrafish embryos, cardiac contractility was measured using
videomicroscopy after CRISPR-mediated knockout of trim55a or
plasmid overexpression of TRIM55 WT or E140K. Genes related to muscle
contraction and cardiac stress were highly regulated in Trim55
E140K/− cardiomyocytes. When compared to the WT/WT cells, the variant
cells demonstrated reduced viability, significant hypertrophic response
to isoproterenol, p21 protein overexpression and impaired cell cycle
progression. In zebrafish embryos, the deletion of trim55a or
overexpression of TRIM55 E140K reduced cardiac contractility as compared
to embryos with wildtype genotype or overexpression of WT TRIM55,
respectively.

Conclusions

A previously uncharacterized TRIM55 E140K variant demonstrated a number of functional implications for cardiomyocyte functions in vitro and in vivo. These findings suggest a novel role for TRIM55 polymorphism in predisposing to heart failure.


Senast uppdaterad 2020-06-04 vid 09:27