Deep sequencing of atrial fibrillation patients with mitral valve regurgitation shows no evidence of mosaicism but reveals novel rare germline variants

Gregers, Emilie; Ahlberg, Gustav; Christensen, Thea; Jabbari, Javad; Larsen, Kirstine O.; Herfelt, Cecilie; Henningsen, Knud W.; Andreasen, Laura; Thiis, Jens J.; Lund, Jens Otto; Holme, Susanne; Haunsø, Stig; Bentzen, Bo Hjorth; Schmitt, Nicole; Svendsen, Jesper Hastrup; Olesen, Morten S.

doi:10.1016/j.hrthm.2017.05.027

Cited by 12 publications

(11 citation statements)

References 30 publications

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“…Interestingly, Cand2 has been linked to atrial fibrillation susceptibility using expression quantitative trait loci mapping, suggesting that it might play an important role in atrial myocytes as well. Increased levels of Cand2 correlated with a higher incidence of atrial fibrillation (Sinner et al, 2014;Wei et al, 2016;Gregers et al, 2017), suggesting that Cand2 might drive pathological remodeling in the atrium.…”

Section: Discussionmentioning

confidence: 99%

Muscle specific translational control of Cand2 by mTORC1 regulates adverse cardiac remodeling

Górska

Sandmann

Riechert

et al. 2020

Preprint

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The mechanistic target of rapamycin (mTOR) is a key regulator of pathological remodeling in the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of mTOR in cardiomyocytes is protective, however, a detailed role of mTOR in translational regulation of specific mRNA networks in the diseased heart is largely unknown. A cardiomyocyte genome-wide sequencing approach was used to define mTOR-dependent post-transcriptional gene expression control at the level of mRNA translation. This approach identified the muscle-specific protein Cullin-associated NEDD8-dissociated protein 2 (Cand2) as a translationally upregulated gene, dependent on the activity of mTOR. Deletion of Cand2 protects the myocardium against pathological remodeling. Mechanistically, we found that Cand2 links mTOR signaling to pathological cell growth by increasing Grk5 protein expression. Our data suggest that cell-type-specific targeting of mTOR might have therapeutic value for adverse pathological cardiac remodeling.

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Section: Discussionmentioning

confidence: 99%

Muscle specific translational control of Cand2 by mTORC1 regulates adverse cardiac remodeling

Górska

Sandmann

Riechert

et al. 2020

Preprint

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“…Right atrial (RA) posterior wall tissue biopsies were obtained from unrelated Caucasian patients undergoing open-heart surgery for mitral valve replacement or repair at the University Hospital of Copenhagen (Rigshospitalet), as previously described [22]. From these, six patients with AF sustained for at least two months were selected.…”

Section: Patients and Tissue Samplesmentioning

confidence: 99%

Investigating gene-microRNA networks in atrial fibrillation patients with mitral valve regurgitation

et al. 2020

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Background Atrial fibrillation (AF) is predicted to affect around 17.9 million individuals in Europe by 2060. The disease is associated with severe electrical and structural remodelling of the heart, and increased the risk of stroke and heart failure. In order to improve treatment and find new drug targets, the field needs to better comprehend the exact molecular mechanisms in these remodelling processes. Objectives This study aims to identify gene and miRNA networks involved in the remodelling of AF hearts in AF patients with mitral valve regurgitation (MVR). Methods Total RNA was extracted from right atrial biopsies from patients undergoing surgery for mitral valve replacement or repair with AF and without history of AF to test for differentially expressed genes and miRNAs using RNA-sequencing and miRNA microarray. In silico predictions were used to construct a mRNA-miRNA network including differentially expressed mRNAs and miRNAs. Gene and chromosome enrichment analysis were used to identify molecular pathways and high-density AF loci. Results We found 644 genes and 43 miRNAs differentially expressed in AF patients compared to controls. From these lists, we identified 905 pairs of putative miRNA-mRNA interactions, including 37 miRNAs and 295 genes. Of particular note, AF-associated miR-130b-3p, miR-338-5p and miR-208a-3p were differentially expressed in our AF tissue samples. These miRNAs are predicted regulators of several differentially expressed genes associated with

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“…In this issue of Heart Rhythm, Gregors et al 17 examined the prevalence of somatic variants in 110 AF candidate genes in 44 patients undergoing surgery for mitral valve regurgitation (MVR). This single-center study of patients with a presurgical history of AF consented to left atrial (LA) posterior wall biopsy during surgery for NGS.…”

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confidence: 99%

“…Functional characterization of a Kv7.1-G272S genetic variant was performed in Xenopus oocytes, which showed a gain-of-function mutation contributing to the AF phenotype. Gregors et al 17 concluded that “somatic variants do not play a major role in the pathogenesis of AF.”…”

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Germline versus somatic mutations in genetic atrial fibrillation

McCauley

Darbar

2017

Heart Rhythm

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Deep sequencing of atrial fibrillation patients with mitral valve regurgitation shows no evidence of mosaicism but reveals novel rare germline variants

Cited by 12 publications

References 30 publications

Muscle specific translational control of Cand2 by mTORC1 regulates adverse cardiac remodeling

Muscle specific translational control of Cand2 by mTORC1 regulates adverse cardiac remodeling

Investigating gene-microRNA networks in atrial fibrillation patients with mitral valve regurgitation

Germline versus somatic mutations in genetic atrial fibrillation

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