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

被引:2
作者
Burkart, Valentin [1 ,8 ]
Kowalski, Kathrin [1 ]
Disch, Alina [1 ]
Hilfiker-Kleiner, Denise [2 ,9 ]
Lal, Sean [3 ]
dos Remedios, Cristobal [4 ]
Perrot, Andreas [5 ]
Zeug, Andre [6 ]
Ponimaskin, Evgeni [6 ]
Kosanke, Maike [7 ]
Dittrich-Breiholz, Oliver [7 ]
Kraft, Theresia [1 ]
Montag, Judith [1 ]
机构
[1] Hannover Med Sch, Inst Mol & Cell Physiol, Hannover, Germany
[2] Hannover Med Sch, Clin Cardiol & Angiol, Hannover, Germany
[3] Univ Sydney, Fac Med & Hlth, Sch Med Sci, Sydney, Australia
[4] Victor Chang Cardiac Res Inst, Mechanosensory Biophys Lab, Darlinghurst, NSW, Australia
[5] Charite Univ Med Berlin, Expt & Clin Res Ctr, Berlin, Germany
[6] Hannover Med Sch, Inst Neurophysiol, Hannover, Germany
[7] Hannover Med Sch, Res Core Unit Genom, Hannover, Germany
[8] Carl Neuberg Str 1, D-30625 Hannover, Germany
[9] Philipps Univ Marburg, Inst Cardiovasc Complicat Pregnancy & Oncol Therap, Marburg, Germany
关键词
Hypertrophic cardiomyopathy; cMyBP-C haploinsufficiency; Nonsense mediated mRNA decay; UPF3B; MESSENGER-RNA DECAY; EXON-JUNCTION COMPLEX; UBIQUITIN-PROTEASOME SYSTEM; SPLICE DONOR SITE; EXPRESSION PATTERNS; GENE-EXPRESSION; BINDING; PROTEIN; MUTATIONS; DYSFUNCTION;
D O I
10.1016/j.yjmcc.2023.09.008
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 socalled haploinsufficiency most likely contributes to disease development. We analyzed mechanisms underlying haploinsufficiency using cardiac tissue from HCM-patients with truncation mutations in MYBPC3 (MYBPC3trunc). 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 NMDcomponents. Among them, Up-frameshift protein UPF3B, a regulator of NMD was upregulated in MYBPC3trunc 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.
引用
收藏
页码:26 / 37
页数:12
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