Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis
| Autor: | Soraya Boucherit, Damien Bonnet, Lazaro Lorenzo, Raphaelle Quint, Serkan Belkaya, Laurent Abel, Aurélie Cobat, Yuval Itan, Fanny Bajolle, Amy R Kontorovich, Cecile Stoven, Minji Byun, Shen-Ying Zhang, Bruce D. Gelb, Sylvie Di Filippo, Rebecca Josowitz, Sonia Mulero-Navarro, Jean-Laurent Casanova |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Pathology medicine.medical_specialty Myocarditis Viral Myocarditis viruses Induced Pluripotent Stem Cells Cardiomyopathy 030204 cardiovascular system & hematology Compound heterozygosity Virus TNNI3 03 medical and health sciences 0302 clinical medicine Immunity Interferon Medicine Humans Myocytes Cardiac business.industry medicine.disease Enterovirus B Human Toll-Like Receptor 3 030104 developmental biology STAT1 Transcription Factor Case-Control Studies Immunology Host-Pathogen Interactions Female Cardiology and Cardiovascular Medicine business Cardiomyopathies medicine.drug |
| Zdroj: | Journal of the American College of Cardiology. 69(13) |
| ISSN: | 1558-3597 |
| Popis: | Background Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM. Objectives This study sought to evaluate the hypothesis that human genetic factors may underlie AVM in previously healthy children. Methods We tested the role of TLR3-IFN immunity using human induced pluripotent stem cell-derived cardiomyocytes. We then performed whole-exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral causes. Results We found that TLR3- and STAT1-deficient cardiomyocytes were not more susceptible to Coxsackie virus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-α/β and IFN-α/β-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-α did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-α/β-related genes. Surprisingly, we found that homozygous but not heterozygous rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic (homozygous or compound heterozygous) nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3). Conclusions Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections in children. |
| Databáze: | OpenAIRE |
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