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| Item Type: | Article |
|---|---|
| Title: | Nonsense mediated decay factor UPF3B is associated with cMyBP-C haploinsufficiency in hypertrophic cardiomyopathy patients |
| Creators Name: | Burkart, V., Kowalski, K., Disch, A., Hilfiker-Kleiner, D., Lal, S., Dos Remedios, C., Perrot, A., Zeug, A., Ponimaskin, E., Kosanke, M., Dittrich-Breiholz, O., Kraft, T. and Montag, J. |
| Abstract: | Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease. Up to 40% of cases are associated with heterozygous mutations in myosin binding protein C (cMyBP-C, MYBPC3). Most of these mutations lead to premature termination codons (PTC) and patients show reduction of functional cMyBP-C. This so-called haploinsufficiency most likely contributes to disease development. We analyzed mechanisms underlying haploinsufficiency using cardiac tissue from HCM-patients with truncation mutations in MYBPC3 (MYBPC3(trunc)). We compared transcriptional activity, mRNA and protein expression to donor controls. To differentiate between HCM-specific and general hypertrophy-induced mechanisms we used patients with left ventricular hypertrophy due to aortic stenosis (AS) as an additional control. We show that cMyBP-C haploinsufficiency starts at the mRNA level, despite hypertrophy-induced increased transcriptional activity. Gene set enrichment analysis (GSEA) of RNA-sequencing data revealed an increased expression of NMD-components. Among them, Up-frameshift protein UPF3B, a regulator of NMD was upregulated in MYBPC3(trunc) patients and not in AS-patients. Strikingly, we show that in sarcomeres UPF3B but not UPF1 and UPF2 are localized to the Z-discs, the presumed location of sarcomeric protein translation. Our data suggest that cMyBP-C haploinsufficiency in HCM-patients is established by UPF3B-dependent NMD during the initial translation round at the Z-disc. |
| Keywords: | Hypertrophic Cardiomyopathy, cMyBP-C Haploinsufficiency, Nonsense Mediated mRNA Decay, UPF3B |
| Source: | Journal of Molecular and Cellular Cardiology |
| ISSN: | 0022-2828 |
| Publisher: | Elsevier |
| Volume: | 185 |
| Page Range: | 26-37 |
| Date: | December 2023 |
| Official Publication: | https://doi.org/10.1016/j.yjmcc.2023.09.008 |
| PubMed: | View item in PubMed |
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