TGFβ-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy.
TGFβ-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy.
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DOI：
10.1002/jcb.24058
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发表时间：
2012-06
影响因子：
4
通讯作者：
Ackerman, Michael J.
中科院分区：
文献类型：
--
作者：
Bos, J. Martijn;Subramaniam, Malayannan;Hawse, John R.;Christiaans, Imke;Rajamannan, Nalini M.;Maleszewski, Joseph J.;Edwards, William D.;Wilde, Arthur A. M.;Spelsberg, Thomas C.;Ackerman, Michael J.
肥厚型心肌病（HCM）是最常见的遗传性心血管疾病。最近的一项研究表明，雄性KLF 10编码的TGFβ诱导早期基因1敲除小鼠（TIEG-/-）发生HCM，PTTG 1编码的垂体肿瘤转化基因1上调13倍。我们假设TIEG 1可能是人类基因型阴性HCM发病机制中的一个新的候选基因，可能是通过失去其对PTTG 1表达的抑制。使用DHPLC和直接DNA测序分析来自两个独立HCM中心的923名无关患者的队列TIEG的4个翻译外显子中的突变。进行定点诱变以克隆新的变体。TIEG 1突变对SMAD 7和PTTG 1启动子的影响使用瞬时转染和内切酶测定进行了研究。通过免疫组织化学（IHC）研究了心脏组织中PTTG 1表达的变化，以确定肥厚性疾病中PTTG 1蛋白的水平。在6例患者中发现了6个新的TIEG 1错义突变（2例男性/4例女性，诊断时平均年龄56.2 ± 23岁，MLVWT 20.8 ± 4 mm）。与WT TIEG 1相比，5个TIEG 1突变体显著增加了PTTG 1启动子功能，类似于TIEG 1-/--小鼠。通过免疫组化，PTTG 1蛋白表达在多种肥厚性心脏病模型中显著增加，包括与正常心脏相比的TIEG 1突变阳性HCM。这是第一篇将TIEG 1突变与人类疾病联系起来的论文，发现了6种新的HCM相关变体。功能测定表明PTTG 1在TIEG 1介导的HCM的发病机制中的作用。PTTG 1的上调似乎是肥厚性心脏病（包括TIEG 1介导的HCM）的常见途径。
Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease. A recent study showed that male KLF10-encoded TGFβ Inducible Early Gene-1 knock-out mice (TIEG-/-) develop HCM with 13-fold up-regulation of PTTG1-encoded pituitary tumor-transforming gene 1. We hypothesized TIEG1 could be a novel candidate gene in the pathogenesis of genotype negative HCM in humans, possibly through a loss of its repression on PTTG1 expression. A cohort of 923 unrelated patients from two independent HCM centers was analyzed for mutations in TIEG's 4 translated exons using DHPLC and direct DNA-sequencing. Site directed mutagenesis was performed to clone novel variants. The effect of TIEG1 mutations on SMAD7 and PTTG1 promoters was studied using transient transfection and luciferase-assays. Altered expression of PTTG1 in cardiac tissue was studied by immunohistochemistry (IHC) to determine levels of PTTG1 protein in hypertrophic diseases. Six novel TIEG1 missense mutations were discovered in 6 patients (2 males/4 females, mean age at diagnosis 56.2 ± 23 years, MLVWT 20.8 ± 4 mm). Compared to WT TIEG1, 5 TIEG1 mutants significantly increased PTTG1 promoter function similar to TIEG1-/--mice. By IHC, PTTG1-protein expression was significantly increased in multiple models of hypertrophic cardiac disease, including TIEG1-mutation positive HCM compared to normal hearts. This is the first paper to associate mutations in TIEG1 to human disease with the discovery of 6 novel, HCM-associated variants. Functional assays suggest a role for PTTG1 in the pathogenesis of TIEG1-mediated HCM. Up-regulation of PTTG1 seems to be a common pathway in hypertrophic heart disease, including TIEG1-mediated HCM.
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影响因子：
4
作者：
Johnsen, SA;Subramaniam, M;Spelsberg, TC
通讯作者：
Spelsberg, TC
影响因子：
64.5
作者：
GEISTERFERLOWRANCE, AAT;KASS, S;SEIDMAN, JG
通讯作者：
SEIDMAN, JG
影响因子：
4
作者：
Rajamannan, Nalini M.;Subramaniam, Malayannan;Spelsberg, Thomas C.
通讯作者：
Spelsberg, Thomas C.
影响因子：
4.1
作者：
Hawse, J. R.;Iwaniec, U. T.;Subramaniam, M.
通讯作者：
Subramaniam, M.
影响因子：
8.9
作者：
Binder, J;Ommen, SR;Ackerman, MJ
通讯作者：
Ackerman, MJ