Hershberger Ray E, Pinto Jose Renato, Parks Sharie B, Kushner Jessica D, Li Duanxiang, Ludwigsen Susan, Cowan Jason, Morales Ana, Parvatiyar Michelle S, Potter James D
Division of Cardiovascular Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Circ Cardiovasc Genet. 2009 Aug;2(4):306-13. doi: 10.1161/CIRCGENETICS.108.846733. Epub 2009 May 15.
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 6 TNNT2 protein-altering variants in 9 probands, all who had early onset, aggressive disease. Additional family members of mutation carriers were then studied when available. Four of the 9 probands had DCM without a family history, and 5 probands had familial DCM. Only 1 mutation (Lys210del) could be attributed as definitively causative from previous reports. Four of the 5 missense mutations were novel (Arg134Gly, Arg151Cys, Arg159Gln, and Arg205Trp), and one was previously reported with hypertrophic cardiomyopathy (Glu244Asp). Based on the clinical, pedigree, and molecular genetic data, these 5 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 Ca(2+) 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.
心血管遗传医学的一个关键问题是确定一个假定的突变是否确实会导致扩张型心肌病（DCM）。这至关重要，因为遗传性DCM通常表现为晚期、危及生命的疾病，对已知携带该突变的亲属进行早期干预可能可预防该病。
我们最近对313例DCM先证者进行了心脏肌钙蛋白T基因TNNT2的双向重测序。我们在9例先证者中鉴定出6个TNNT2蛋白改变变体，所有这些先证者均患有早发性、侵袭性疾病。然后在有条件时对突变携带者的其他家庭成员进行了研究。9例先证者中有4例无DCM家族史，5例先证者有家族性DCM。根据先前的报告，只有1个突变（Lys210del）可明确归因于致病原因。5个错义突变中有4个是新的（Arg134Gly、Arg151Cys、Arg159Gln和Arg205Trp），1个先前报道与肥厚型心肌病有关（Glu244Asp）。基于临床、家系和分子遗传学数据，认为这5个突变可能或很可能致病。为了进一步阐明它们潜在的病理生理影响，我们在用突变型肌钙蛋白T蛋白重构的心肌细胞中对这些突变进行了功能研究。我们观察到力产生的Ca(2+)敏感性降低，这是DCM的一个标志，支持这些突变致病的结论。
我们得出结论认为，临床、家系、分子遗传学和功能数据相结合加强了对DCM中TNNT2突变的解释。
