Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis
Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis
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DOI：
10.1016/j.jacc.2017.01.043
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发表时间：
2017-04-04
影响因子：
24
通讯作者：
Casanova, Jean-Laurent
中科院分区：
文献类型：
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作者：
Belkaya, Serkan;Kontorovich, Amy R.;Casanova, Jean-Laurent
背景心肌炎是各种病毒感染后引起的心肌炎症。鉴于致病性病毒感染很常见，为什么儿童很少发生危及生命的急性病毒性心肌炎（AVM）尚不清楚。遗传病变可能是这种易感性的基础。小鼠遗传学研究表明，干扰素（IFN）-α/β免疫缺陷增加病毒诱导的心肌炎的易感性。此外，在人类TLR 3，一个强有力的诱导IFN的变化，提出了潜在的AVM。APPLICATIVES本研究试图评估的假设，人类遗传因素可能是潜在的AVM在以前健康的children.METHODS我们测试了TLR 3-IFN免疫的作用，使用人类诱导多能干细胞衍生的心肌细胞。然后，我们进行了全外显子组测序的42个无关的儿童急性心肌炎（AM），一些已证实的病毒causes.Results我们发现，TLR 3和STAT 1缺陷的心肌细胞并不比对照细胞更容易受到科萨基病毒B3（CVB 3）感染。此外，CVB 3在对照心肌细胞中不诱导IFN-α/β和IFN-α/β刺激的基因。最后，外源性IFN-α基本上不能保护心肌细胞免受CVB 3的侵害。我们没有观察到TLR 3或IFN-α/β相关基因的罕见变异的显著富集。令人惊讶的是，我们发现，与健康个体（p = 2.22E-03）或患有其他疾病的患者（p = 1.08E-04）相比，AM-AVM患者中与遗传性心肌病相关的基因中的纯合但非杂合罕见变异显著富集。42例患者中有7例（16.7%）在6个心肌病相关基因（BAG 3，DSP，PKP 2，RYR 2，SCN 5A或TNNI 3）中携带罕见的双等位基因（纯合子或复合杂合子）非同义或剪接位点变异。(C)2017年美国心脏病学院基金会。
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)-alpha/beta 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-alpha/beta and IFN-alpha/beta-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-alpha did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3-or IFN-alpha/beta-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. (C) 2017 by the American College of Cardiology Foundation.