谷歌浏览器插件
订阅小程序
在清言上使用

Burst-Like Transcription of Sarcomeric Genes in Hypertrophic Cardiomyopathy

Biophysical journal(2021)

引用 0|浏览19
暂无评分
摘要
Hypertrophic cardiomyopathy (HCM) is mostly caused by heterozygous mutations in sarcomeric genes. About 90% of mutation-positive patients encode for mutations in myosin binding protein C (cMyBP-C, MYBPC3), β-myosin heavy chain (β-MyHC, MYH7), cardiac troponin T (cTnT, TNNT2) and cardiac troponin I (cTnI, TNNI3). In previous studies, we showed a large variability in force generation between individual cardiomyocytes from HCM-patients with mutations in β-MyHC,cMyBP-C and cTnI. We hypothesized that this so-called contractile imbalance may provide a common pathomechanism how different functional effects of different mutations induce similar HCM features. Here we asked whether burst-like transcription of mutant and wildtype alleles from TNNI3 and MYBPC3 might underlie contractile imbalance as shown previously for MYH7. Using single molecule RNA-fluorescence in situ hybridization (smRNA-FISH) on tissue sections from donor controls and HCM-patients with TNNI3-mutation R145W and MYBPC3 truncation mutation c.927-2G>A, we show that burst-like transcription is a common transcriptional mechanism of TNNI3 and MYBPC3. Non-Poisson distributed TNNI3 and MYBPC3-mRNA molecules per cell support this finding. We additionally show that substantial allelic imbalance from cell to cell, as revealed by allele specific single cell RT-PCR analysis for TNNI3, is associated with this burst-like transcription. In the cMyBP-Ctrunc patient, we detected a highly variable distribution of wildtype cMyBP-C from cell to cell presumably associated with burst-like transcription. In summary, we provide evidence that at least three of the four most commonly affected genes in HCM are transcribed burst-like. The random expression of both alleles may lead to highly variable fractions of mutant per wildtype mRNA and wildtype protein from cell to cell. Due to mutation-induced alterations in contractile function this may underlie contractile imbalance between neighboring cardiomyocytes and thereby be one factor that induces hypertrophy, fibrosis and cardiomyocyte disarray in HCM patients.
更多
查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要