Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease.
Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease.
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DOI：
10.1007/s10875-021-01000-y
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发表时间：
2021-07
影响因子：
9.1
通讯作者：
Chevillard C
中科院分区：
文献类型：
--
作者：
Ouarhache M;Marquet S;Frade AF;Ferreira AM;Ianni B;Almeida RR;Nunes JPS;Ferreira LRP;Rigaud VO;Cândido D;Mady C;Zaniratto RCF;Buck P;Torres M;Gallardo F;Andrieux P;Bydlowsky S;Levy D;Abel L;Cardoso CS;Santos-Junior OR;Oliveira LC;Oliveira CDL;Nunes MDC;Cobat A;Kalil J;Ribeiro AL;Sabino EC;Cunha-Neto E;Chevillard C
心肌病是心力衰竭和心源性猝死的重要原因。关于罕见遗传变异在炎症性心肌病中的作用知之甚少。慢性查加斯病心肌病（CCC）是一种在拉丁美洲流行的炎性心肌病，在600万慢性感染原生动物克氏锥虫的患者中有30%发生，而60%没有心脏病（无症状（ASY））。已知细胞因子干扰素-γ和线粒体功能障碍发挥主要致病作用。查加斯病提供了一个独特的模型，以探测涉及炎症性心肌病的遗传变异。我们使用全外显子组测序来研究包含多个恰加斯病病例的核心家族。我们寻找罕见的致病性变异共享的所有家庭成员与CCC，但没有在感染的ASY兄弟姐妹和无关的ASY。我们在所有测试的家族中鉴定了22个不同基因上与CCC相关的杂合致病性变体，其中20个是线粒体或炎症相关的，后者大多数参与促炎细胞因子的产生。值得注意的是，在用二氢乳清酸脱氢酶布喹那（在一个家族中显示功能丧失变体的酶）抑制剂处理的人心肌细胞系上与IFN-γ孵育显著降低了线粒体膜电位（Δ Δ M），表明线粒体功能障碍。线粒体功能障碍和炎症可能是遗传决定的CCC，由罕见的遗传变异驱动。我们假设CCC连锁的遗传变异增加了心肌中线粒体对IFN-γ诱导的损伤的易感性，导致查加斯病的心肌病表型。这种机制也可能在其他炎症性心肌病中发挥作用。在线版本包含补充材料，可通过10.1007/s10875-021-01000-y获得。
Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-γ and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy. We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY. We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related – most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-γ on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (ΔψM), indicating mitochondrial dysfunction. Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies. The online version contains supplementary material available at 10.1007/s10875-021-01000-y.
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影响因子：
--
作者：
Marston S
通讯作者：
Marston S
影响因子：
3.7
作者：
Khan R;Lee JE;Yang YM;Liang FX;Sehgal PB
通讯作者：
Sehgal PB
影响因子：
4.5
作者：
Kohda M;Tokuzawa Y;Kishita Y;Nyuzuki H;Moriyama Y;Mizuno Y;Hirata T;Yatsuka Y;Yamashita-Sugahara Y;Nakachi Y;Kato H;Okuda A;Tamaru S;Borna NN;Banshoya K;Aigaki T;Sato-Miyata Y;Ohnuma K;Suzuki T;Nagao A;Maehata H;Matsuda F;Higasa K;Nagasaki M;Yasuda J;Yamamoto M;Fushimi T;Shimura M;Kaiho-Ichimoto K;Harashima H;Yamazaki T;Mori M;Murayama K;Ohtake A;Okazaki Y
通讯作者：
Okazaki Y
影响因子：
29
作者：
Arroyo JD;Jourdain AA;Calvo SE;Ballarano CA;Doench JG;Root DE;Mootha VK
通讯作者：
Mootha VK
影响因子：
24
作者：
Belkaya, Serkan;Kontorovich, Amy R.;Casanova, Jean-Laurent
通讯作者：
Casanova, Jean-Laurent