@article{BrodehlMeshkovMyasnikovetal.2021, author = {Brodehl, Andreas and Meshkov, Alexey and Myasnikov, Roman and Kiseleva, Anna and Kulikova, Olga and Klauke, B{\"a}rbel and Sotnikova, Evgeniia and Stanasiuk, Caroline and Divashuk, Mikhail and Pohl, Greta Marie and Kudryavtseva, Maria and Klingel, Karin and Gerull, Brenda and Zharikova, Anastasia and Gummert, Jan and Koretskiy, Sergey and Schubert, Stephan and Mershina, Elena and G{\"a}rtner, Anna and Pilus, Polina and Laser, Kai Thorsten and Sinitsyn, Valentin and Boytsov, Sergey and Drapkina, Oxana and Milting, Hendrik}, title = {Hemi- and homozygous loss-of-function mutations in DSG2 (desmoglein-2) cause recessive arrhythmogenic cardiomyopathy with an early onset}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {7}, issn = {1422-0067}, doi = {10.3390/ijms22073786}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285279}, year = {2021}, abstract = {About 50\% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2-c.378+1G>T) in the first patient and a nonsense mutation (DSG2-p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.}, language = {en} } @article{BrodehlMiltingGerull2021, author = {Brodehl, Andreas and Milting, Hendrik and Gerull, Brenda}, title = {Special Issue "Cardiovascular Genetics"}, series = {Genes}, volume = {12}, journal = {Genes}, number = {4}, issn = {2073-4425}, doi = {10.3390/genes12040479}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234229}, year = {2021}, abstract = {No abstract available}, language = {en} } @article{GerullBrodehl2021, author = {Gerull, Brenda and Brodehl, Andreas}, title = {Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy}, series = {Current Heart Failure Reports}, volume = {18}, journal = {Current Heart Failure Reports}, number = {6}, issn = {1546-9549}, doi = {10.1007/s11897-021-00532-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-269916}, pages = {378-390}, year = {2021}, abstract = {Purpose of Review Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy young adults. Mutations in genes encoding for cellular junctions can be found in about half of the patients. However, disease onset and severity, risk of arrhythmias, and outcome are highly variable and drug-targeted treatment is currently unavailable. Recent Findings This review focuses on advances in clinical risk stratification, genetic etiology, and pathophysiological concepts. The desmosome is the central part of the disease, but other intercalated disc and associated structural proteins not only broaden the genetic spectrum but also provide novel molecular and cellular insights into the pathogenesis of ACM. Signaling pathways and the role of inflammation will be discussed and targets for novel therapeutic approaches outlined. Summary Genetic discoveries and experimental-driven preclinical research contributed significantly to the understanding of ACM towards mutation- and pathway-specific personalized medicine.}, language = {en} } @article{JanzZinkCirnuetal.2021, author = {Janz, Anna and Zink, Miriam and Cirnu, Alexandra and Hartleb, Annika and Albrecht, Christina and Rost, Simone and Klopocki, Eva and G{\"u}nther, Katharina and Edenhofer, Frank and Erg{\"u}n, S{\"u}leyman and Gerull, Brenda}, title = {CRISPR/Cas9-edited PKP2 knock-out (JMUi001-A-2) and DSG2 knock-out (JMUi001-A-3) iPSC lines as an isogenic human model system for arrhythmogenic cardiomyopathy (ACM)}, series = {Stem Cell Research}, volume = {53}, journal = {Stem Cell Research}, doi = {10.1016/j.scr.2021.102256}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259846}, pages = {102256}, year = {2021}, abstract = {Arrhythmogenic cardiomyopathy (ACM) is characterized by fibro-fatty replacement of the myocardium, heart failure and life-threatening ventricular arrhythmias. Causal mutations were identified in genes encoding for proteins of the desmosomes, predominantly plakophilin-2 (PKP2) and desmoglein-2 (DSG2). We generated gene-edited knock-out iPSC lines for PKP2 (JMUi001-A-2) and DSG2 (JMUi001-A-3) using the CRISPR/Cas9 system in a healthy control iPSC background (JMUi001A). Stem cell-like morphology, robust expression of pluripotency markers, embryoid body formation and normal karyotypes confirmed the generation of high quality iPSCs to provide a novel isogenic human in vitro model system mimicking ACM when differentiated into cardiomyocytes.}, language = {en} } @article{ShemerMekiesBenJehudaetal.2021, author = {Shemer, Yuval and Mekies, Lucy N. and Ben Jehuda, Ronen and Baskin, Polina and Shulman, Rita and Eisen, Binyamin and Regev, Danielle and Arbustini, Eloisa and Gerull, Brenda and Gherghiceanu, Mihaela and Gottlieb, Eyal and Arad, Michael and Binah, Ofer}, title = {Investigating LMNA-related dilated cardiomyopathy using human induced Pluripotent Stem Cell-derived cardiomyocytes}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {15}, issn = {1422-0067}, doi = {10.3390/ijms22157874}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285673}, year = {2021}, abstract = {LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients' induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (I\(_f\)) density; (2) prolonged action potential duration and increased L-type Ca\(^{2+}\) current (I\(_{Ca,L}\)) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na\(^+\)/Ca\(^{2+}\) exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.}, language = {en} }