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Nonsense mediated decay factor UPF3B is associated with cMyBP-C haploinsufficiency in hypertrophic cardiomyopathy patients

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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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