Clinical and functional characterization of TNNT2 mutations identified in patients with dilated cardiomyopathy.
Clinical and functional characterization of TNNT2 mutations identified in patients with dilated cardiomyopathy.
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DOI：
10.1161/circgenetics.108.846733
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发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
Potter JD
中科院分区：
文献类型：
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作者：
Hershberger RE;Pinto JR;Parks SB;Kushner JD;Li D;Ludwigsen S;Cowan J;Morales A;Parvatiyar MS;Potter JD
心血管遗传医学的一个关键问题是确定假定的突变是否确实导致扩张型心肌病（DCM）。这是至关重要的，因为遗传性DCM，通常表现为晚期，危及生命的疾病，可以通过对已知携带突变的亲属进行早期干预来预防。我们最近对313例DCM先证者进行了心肌肌钙蛋白T基因TNNT2的双向重测序。我们在9名先证者中发现了6种TNNT2蛋白改变变体，所有这些先证者都患有早发性侵袭性疾病。然后在可用时研究突变携带者的其他家庭成员。9名先证者中有4名患有DCM，无家族史，5名患有家族性DCM。只有一个突变（Lys210del）可以归因为明确的因果关系，从以前的报告。5个错义突变中有4个是新发现的（Arg134Gly，Arg151Cys，Arg159Gln，Arg205Trp），1个是先前报道的肥厚型心肌病（Glu244Asp）。根据临床、系谱和分子遗传学数据，认为这五种突变可能或很可能导致疾病。为了进一步阐明其潜在的病理生理影响，我们进行了功能研究，这些突变与突变肌钙蛋白T蛋白重建心肌细胞。我们观察到力发展的Ca2+敏感性降低，这是DCM的标志，支持这些突变是致病的结论。我们的结论是，临床，系谱，分子遗传学和功能数据的结合加强了DCM中TNNT2突变的解释。
A key issue for cardiovascular genetic medicine is ascertaining if a putative mutation indeed causes dilated cardiomyopathy (DCM). This is critically important as genetic DCM, usually presenting with advanced, life-threatening disease, may be preventable with early intervention in relatives known to carry the mutation. We recently undertook bidirectional resequencing of TNNT2, the cardiac troponin T gene, in 313 probands with DCM. We identified six TNNT2 protein-altering variants in nine probands, all who had early onset, aggressive disease. Additional family members of mutation carriers were then studied when available. Four of the nine probands had DCM without a family history, and five had familial DCM. Only one mutation (Lys210del) could be attributed as definitively causative from prior reports. Four of the five missense mutations were novel (Arg134Gly, Arg151Cys, Arg159Gln, Arg205Trp), and one was previously reported with hypertrophic cardiomyopathy (Glu244Asp). Based on the clinical, pedigree and molecular genetic data these five mutations were considered possibly or likely disease causing. To further clarify their potential pathophysiologic impact, we undertook functional studies of these mutations in cardiac myocytes reconstituted with mutant troponin T proteins. We observed decreased Ca2+ sensitivity of force development, a hallmark of DCM, in support of the conclusion that these mutations are disease-causing. We conclude that the combination of clinical, pedigree, molecular genetic and functional data strengthen the interpretation of TNNT2 mutations in DCM.