Sodium channel mutations and susceptibility to heart failure and atrial fibrillation
Sodium channel mutations and susceptibility to heart failure and atrial fibrillation
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DOI：
10.1001/jama.293.4.447
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发表时间：
2005-01-26
影响因子：
120.7
通讯作者：
Anderson, JL
中科院分区：
文献类型：
--
作者：
Olson, TM;Michels, VV;Anderson, JL
背景扩张型心肌病(DCM)是一种遗传异质性疾病，可导致心力衰竭和节律紊乱。大多数已鉴定的DCM基因编码收缩装置和细胞骨架的结构蛋白。最近，在扩张型心肌病患者中发现了钙和钾调节的遗传缺陷，这意味着另一种疾病机制。目的鉴定扩张型心肌病新基因，确定扩张型心肌病队列中该基因的突变谱，并确定遗传该基因突变的亲属中扩张型心肌病的频率。设计、设置和参与者在一个多代人家系中对染色体3p上的扩张型心肌病基因座进行精细定位，并对1987-2004年间梅奥诊所前瞻性发现的156例无关的扩张型心肌病先证者进行突变扫描。亲属进行超声心动图、心电图和DNA样本采集。主要结果衡量已发现的突变与心脏表型的相关性。结果精细的基因定位显示，编码心脏钠通道的SCN5A是一个候选基因。突变扫描发现了一个错义突变(D1275N)，该突变与扩张型心肌病、房颤、自律性受损和传导延迟等年龄相关的可变表达表型共分离。在DCM中，在无亲缘关系的先证者中发现了队列、额外的错义(T2201、R814W、D1595H)和截断(2550-2551insTG)SCN5A突变，这些突变与心脏病分离或引起从头开始。在携带SCN5A突变的个体中，27%有DCM的早期特征(确诊时平均年龄为20.3岁)，38%有DCM(确诊时平均年龄为47.9岁)，43%有房颤(确诊时平均年龄为27.8岁)。相似甚至相同的突变可能会导致心力衰竭、心律失常或两者兼而有之。
Context Dilated cardiomyopathy (DCM), a genetically heterogeneous disorder, causes heart failure and rhythm disturbances. The majority of identified DCM genes encode structural proteins of the contractile apparatus and cytoskeleton. Recently, genetic defects in,calcium and potassium regulation have been discovered in patients with DCM, implicating an alternative disease mechanism. The full spectrum of genetic defects in DCM, however, has not been established.Objectives To identify a novel gene for DCM at a previously mapped locus, define the spectrum of mutations in this gene within a DCM cohort and determine the frequency of DCM among relatives inheriting a mutation in this gene.Design, Setting, and Participants Refined mapping of a DCM locus on chromosome 3p,in a multigenerational family and mutation scanning in 156 unrelated probands with DCM, prospectively identified at the Mayo Clinic between 1987 and 2004. Relatives underwent screening echocardiography and electrocardiography and DNA sample procurement.Main Outcome Measure Correlation of identified mutations with cardiac phenotype.Results Refined locus mapping revealed SCN5A, encoding the cardiac sodium channel, as a candidate gene. Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay. In the DCM, cohort, additional missense (T2201, R814W, D1595H) and truncation (2550-2551insTG) SCN5A mutations, segregating with cardiac disease or arising de novo, were discovered in unrelated probands. Among individuals with an SCN5A mutation 27% had early features of DCM (mean age at diagnosis, 20.3 years), 38% had DCM (mean age at diagnosis, 47.9 years), and 43% had atrial fibrillation (mean age at diagnosis, 27.8 years).Conclusions Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation. Similar or even identical mutations may lead to heart failure, arrhythmia, or both.