Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy
Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy
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DOI：
10.1016/j.ahj.2008.01.026
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发表时间：
2008-07-01
影响因子：
4.8
通讯作者：
Hershberger, Ray E.
中科院分区：
文献类型：
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作者：
Parks, Sharie B.;Kushner, Jessica D.;Hershberger, Ray E.
背景：Lamin A/C突变是扩张型心肌病(DCM)的一个公认的原因，尽管它们的频率在大量患者中尚未被检测到。本研究旨在检测特发性(IDC)或家族性扩张型心肌病(FDC)患者的LMNA基因突变频率。方法收集324例IDC先证者的临床心血管资料、家族史和血样，其中187例有FDC。对DNA样本进行测序，以确定LMNA的核苷酸改变。结果我们在19个先证者中发现了18个蛋白改变LMNA变异，占所有病例的5.9%(FDC的7.5%；IDC的3.6%)。在18个突变中，11个为错义突变(1个存在于2个家系中)，3个为无义突变，3个为插入/缺失突变，1个为剪接位点突变。传导系统疾病和扩张型心肌病在LMNA变异体携带者中常见。在19个LMNA变异型家系中，有6个家系(32%)至少有1个成员LMNA变异型为阴性。对FDC家系的新观察表明，并不是所有受影响的人都携带可能致病的LMNA突变，这表明一些改变蛋白质的LMNA变体不是致病原因，或者某些比例的FDC可能是由多种致病因素引起的。这些发现需要在FDC研究和分子诊断学中更加谨慎。
Background Lamin A/C mutations are a well-established cause of dilated cardiomyopathy (DCM), although their frequency has not been examined in a large cohort of patients. We sought to examine the frequency of mutations in LMNA, the gene encoding lamin A/C, in patients with idiopathic (IDC) or familial dilated cardiomyopathy (FDC).Methods Clinical cardiovascular data, family histories, and blood samples were collected from 324 unrelated IDC probands, of whom 187 had FDC. DNA samples were sequenced for nucleotide alterations in LMNA. Likely protein-altering mutations were followed up by evaluating additional family members, when possible.Results We identified 18 protein-altering LMNA variants in 19 probands or 5.9% of all cases (7.5% of FDC; 3.6% of IDC). Of the 18 alterations, 11 were missense (one present in 2 kindreds), 3 were nonsense, 3 were insertion/deletions, and I was a splice site alteration. Conduction system disease and DCM were common in carriers of LMNA variants. Unexpectedly, in 6 of the 19 kindreds with a protein-altering LMNA variant (32%), at least one affected family member was negative for the LMNA variant.Conclusions Lamin A/C variants were observed with a frequency of 5.9% in probands with DCM. The novel observation of FDC pedigrees in which not all affected individuals carry the putative disease-causing LMNA mutation suggests that some protein-altering LMNA variants are not causative or that some proportion of FDC may be because of multiple causative factors. These findings warrant increased caution in FDC research and molecular diagnostics.