Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy
Thomas Meyer,Volker Ruppert,Sarah Ackermann,Anette Richter,Andreas Perrot,Silke Sperling,Maximilian G. Posch,Bernhard Maisch,Sabine Pankuweit +8 more
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TLDR
Novel missense mutations in the third immunoglobulin-like domain of myopalladin are identified, which have either no or profound effects on the molecular composition of the sarcomeric apparatus and the protection against DCM.Abstract:
Recently, missense mutations in titin-associated proteins have been linked to the pathogenesis of dilated cardiomyopathy (DCM). The objective of this study was to search for novel disease-associated mutations in the two human titin-binding proteins myopalladin and its amino-terminal-interacting partner cardiac ankyrin-repeat protein (CARP). In a cohort of 255 cases with familial and sporadic DCM, we analyzed the coding regions and all corresponding intron flanks located in the MYPN and CARP-encoding ANKRD1 gene. Two heterozygous missense mutations were detected in the MYPN gene (p.R955W and p.P961L), but neither of these mutations was found in 300 healthy controls. Both mutations were located in the α-actinin-binding region of myopalladin. Endomyocardial biopsies from the p.R955W carrier showed normal subcellular localization of myopalladin and α-actinin in cardiac myocytes, while their regular sarcomeric staining pattern was significantly disrupted in the p.P961L carrier, indicating that disturbed myofibrillogenesis and altered sarcomere assembly are the cause of the disease. In the ANKRD1 gene, we identified synonymous base exchanges (c.108T>C and c.-79C>T, respectively), but no non-synonymous mutations. In summary, we have identified novel missense mutations in the third immunoglobulin-like domain of myopalladin, which have either no or profound effects on the molecular composition of the sarcomere. According to our epidemiological data, the prevalence of ANKRD1 mutations seems to be lower than that of its binding partner myopalladin, indicating the clinical significance of myopalladin for the functional integrity of the sarcomeric apparatus and the protection against DCM.read more
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The physiological role of cardiac cytoskeleton and its alterations in heart failure
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TL;DR: Here, agents that modulate the mechanical function of the sarcomere are reviewed, focusing on emerging compounds that target myosin or the troponin complex.
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Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes.
Katrin Streckfuss-Bömeke,Malte Tiburcy,Andrey Fomin,Xiaojing Luo,Wener Li,Claudia Fischer,Cemil Özcelik,Andreas Perrot,Samuel Sossalla,Jan Haas,Ramon O. Vidal,Sabine Rebs,Sara Khadjeh,Benjamin Meder,Stefan Bonn,Wolfgang A. Linke,Wolfram-Hubertus Zimmermann,Gerd Hasenfuss,Kaomei Guan,Kaomei Guan +19 more
TL;DR: The data demonstrate that iPSC-CMs coupled with EHMs provide a powerful tool for evaluating disease-relevant functional defects and for a deeper mechanistic understanding of alternative splicing-related cardiac diseases.
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Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy.
Satoko Miyatake,Satomi Mitsuhashi,Yukiko K. Hayashi,Enkhsaikhan Purevjav,Atsuko Nishikawa,Eriko Koshimizu,Mikiya Suzuki,Kana Yatabe,Yuzo Tanaka,Katsuhisa Ogata,Satoshi Kuru,Masaaki Shiina,Yoshinori Tsurusaki,Mitsuko Nakashima,Takeshi Mizuguchi,Noriko Miyake,Hirotomo Saitsu,Hirotomo Saitsu,Kazuhiro Ogata,Mitsuru Kawai,Jeffrey A. Towbin,Ikuya Nonaka,Ichizo Nishino,Naomichi Matsumoto +23 more
TL;DR: The results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present, as well as in those with milder, later-onset NM.
Journal ArticleDOI
Rbm20-deficient cardiogenesis reveals early disruption of RNA processing and sarcomere remodeling establishing a developmental etiology for dilated cardiomyopathy
Rosanna Beraldi,Xing Li,Almudena Martinez Fernandez,Santiago Reyes,Frank J. Secreto,Andre Terzic,Timothy M. Olson,Timothy J. Nelson +7 more
TL;DR: Using the pluripotent stem cell platform to model human cardiac disease according to a stage-specific cardiogenic roadmap, a new paradigm of familial DCM pathogenesis is established as a developmental disorder that is patterned during early cardiogenesis and propagated with cellular mechanisms of pathological cardiac remodeling.
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