Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy.
Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy.
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DOI：
10.1007/s00395-011-0205-9
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发表时间：
2011-11
影响因子：
9.5
通讯作者：
Kraft T
中科院分区：
文献类型：
--
作者：
Tripathi S;Schultz I;Becker E;Montag J;Borchert B;Francino A;Navarro-Lopez F;Perrot A;Özcelik C;Osterziel KJ;McKenna WJ;Brenner B;Kraft T
家族性肥厚型心肌病（FHC）是一种常染色体显性遗传疾病，约30%的患者是由β-肌球蛋白重链（β-MHC）基因（MYH 7）的一个等位基因的错义突变引起的。为了阐明家族特异性预后的潜在分子机制，我们确定了突变型与野生型MYH 7-mRNA的相对表达。我们发现了一种迄今未知的突变依赖性MYH 7-mRNA与野生型MYH 7-mRNA的不平等表达，这与β-MHC在蛋白水平上的类似不平等表达相一致。通过特异性限制性消化方法和实时PCR（RT-qPCR）测定突变型与野生型MYH 7-mRNA的相对丰度。14个来自M.分析了12例基因型和临床特征良好的FHC患者的比目鱼肌和心肌。在5名具有突变R723 G的患者中，突变MYH 7-mRNA的分数平均分别为比目鱼肌和心肌中总MYH 7-mRNA的66%和68%。对于突变I736 T、R719 W和V606 M，M.比目鱼肌分别为39、57和29%。对于所有突变，不等丰度在蛋白质水平上相似。重要的是，突变转录本的分数在兄弟姐妹、年轻亲属和相同突变的无关携带者之间是相当的。因此，突变与野生型转录本和蛋白质的不平等表达的程度是每个突变的特征，这意味着顺式作用的调节机制。生物信息学表明mRNA稳定性或剪接效应子受某些突变的影响。有趣的是，我们观察到疾病表达与突变mRNA和蛋白质分数之间的相关性。这有力地表明，突变特异性等位基因失衡代表了FHC的一个新的致病因素。本文的在线版本（doi：10.1007/s 00395 -011-0205-9）包含补充材料，可供授权用户使用。
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which in about 30% of the patients is caused by missense mutations in one allele of the β-myosin heavy chain (β-MHC) gene (MYH7). To address potential molecular mechanisms underlying the family-specific prognosis, we determined the relative expression of mutant versus wild-type MYH7-mRNA. We found a hitherto unknown mutation-dependent unequal expression of mutant to wild-type MYH7-mRNA, which is paralleled by similar unequal expression of β-MHC at the protein level. Relative abundance of mutated versus wild-type MYH7-mRNA was determined by a specific restriction digest approach and by real-time PCR (RT-qPCR). Fourteen samples from M. soleus and myocardium of 12 genotyped and clinically well-characterized FHC patients were analyzed. The fraction of mutated MYH7-mRNA in five patients with mutation R723G averaged to 66 and 68% of total MYH7-mRNA in soleus and myocardium, respectively. For mutations I736T, R719W and V606M, fractions of mutated MYH7-mRNA in M. soleus were 39, 57 and 29%, respectively. For all mutations, unequal abundance was similar at the protein level. Importantly, fractions of mutated transcripts were comparable among siblings, in younger relatives and unrelated carriers of the same mutation. Hence, the extent of unequal expression of mutated versus wild-type transcript and protein is characteristic for each mutation, implying cis-acting regulatory mechanisms. Bioinformatics suggest mRNA stability or splicing effectors to be affected by certain mutations. Intriguingly, we observed a correlation between disease expression and fraction of mutated mRNA and protein. This strongly suggests that mutation-specific allelic imbalance represents a new pathogenic factor for FHC. The online version of this article (doi:10.1007/s00395-011-0205-9) contains supplementary material, which is available to authorized users.
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影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
37.8
作者：
MARON, BJ;GARDIN, JM;BILD, DE
通讯作者：
BILD, DE
影响因子：
14.9
作者：
BECKERANDRE, M;HAHLBROCK, K
通讯作者：
HAHLBROCK, K
DOI：
10.1152/ajpheart.00686.2004
发表时间：
2005-03-01
影响因子：
4.8
作者：
Kirschner, SE;Becker, E;Kraft, T
通讯作者：
Kraft, T
影响因子：
158.5
作者：
Niimura, H;Bachinski, LL;Seidman, CE
通讯作者：
Seidman, CE