Mutations of presenilin genes in dilated cardiomyopathy and heart failure
Mutations of presenilin genes in dilated cardiomyopathy and heart failure
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DOI：
10.1086/509900
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发表时间：
2006-12-01
影响因子：
9.8
通讯作者：
Hershberger, Ray E.
中科院分区：
文献类型：
--
作者：
Li, Duanxiang;Parks, Sharie B.;Hershberger, Ray E.
老年人的两种常见疾病是心力衰竭和阿尔茨海默病（AD）。心衰通常由扩张型心肌病（DCM）引起。家庭中原因不明的DCM最近被证明是由遗传疾病引起的，突出了新发现的疾病机制。阿尔茨海默病是美国老年人最常见的神经退行性疾病。家族性AD通常由早老素1 （PSEN1）或早老素2 （PSEN2）突变引起，这一发现极大地推动了该领域的发展。早老素也在心脏中表达，对心脏发育至关重要。我们假设早老素的突变也可能与DCM有关，他们的发现可能为DCM和心力衰竭的发病机制提供新的见解。对315例DCM患者进行PSEN1和PSEN2序列变异评估。突变阳性的家庭进行了额外的临床、遗传和功能研究。在一个家族中发现了一个新的PSEN1错义突变（Asp333Gly），在另外两个家族中发现了一个PSEN2错义突变（Ser130Leu）。这两种突变都与DCM和心力衰竭分离。PSEN1突变与完全外显率和导致心脏移植或死亡的进展性疾病相关。PSEN2突变显示部分外显率，病情较轻，预后较好。在PSEN1和PSEN2突变携带者培养的皮肤成纤维细胞中，钙信号被改变。这些数据表明PSEN1和PSEN2突变与DCM和心力衰竭有关，并暗示心肌疾病的新机制。
Two common disorders of the elderly are heart failure and Alzheimer disease (AD). Heart failure usually results from dilated cardiomyopathy (DCM). DCM of unknown cause in families has recently been shown to result from genetic disease, highlighting newly discovered disease mechanisms. AD is the most frequent neurodegenerative disease of older Americans. Familial AD is caused most commonly by presenilin 1 (PSEN1) or presenilin 2 (PSEN2) mutations, a discovery that has greatly advanced the field. The presenilins are also expressed in the heart and are critical to cardiac development. We hypothesized that mutations in presenilins may also be associated with DCM and that their discovery could provide new insight into the pathogenesis of DCM and heart failure. A total of 315 index patients with DCM were evaluated for sequence variation in PSEN1 and PSEN2. Families positive for mutations underwent additional clinical, genetic, and functional studies. A novel PSEN1 missense mutation (Asp333Gly) was identified in one family, and a single PSEN2 missense mutation (Ser130Leu) was found in two other families. Both mutations segregated with DCM and heart failure. The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death. The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis. Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers. These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart failure and implicate novel mechanisms of myocardial disease.