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| http://dx.doi.org/10.1172/JCI170196 | DOI Listing |
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Discovery of Titin and Its Role in Heart Function and Disease.
Circ Res
January 2025
Department of Integrative Pathophysiology, Medical Faculty Mannheim, DZHK Partnersite Mannheim-Heidelberg, University of Heidelberg, Germany (S.L.).
This review examines the giant elastic protein titin and its critical roles in heart function, both in health and disease, as discovered since its identification nearly 50 years ago. Encoded by the TTN (titin gene), titin has emerged as a major disease locus for cardiac disorders. Functionally, titin acts as a third myofilament type, connecting sarcomeric Z-disks and M-bands, and regulating myocardial passive stiffness and stretch sensing.
View Article and Find Full Text PDFRegulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer.
J Clin Invest
December 2024
Department of Genetics, Harvard Medical School, Boston, United States of America.
Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure. To understand mechanisms that regulate abundant cardiomyocyte TTN expression we characterized highly conserved intron 1 sequences that exhibited dynamic changes in chromatin accessibility during differentiation of human cardiomyocytes from induced pluripotent stem cells (hiPSC-CMs). Homozygous deletion of these sequences in mice caused embryonic lethality while heterozygous mice demonstrated allele-specific reduction in Ttn expression.
View Article and Find Full Text PDFCardiac Applications of CRISPR/AAV-Mediated Precise Genome Editing.
bioRxiv
December 2024
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
The ability to efficiently make precise genome edits in somatic tissues will have profound implications for gene therapy and basic science. CRISPR/Cas9 mediated homology-directed repair (HDR) is one approach that is commonly used to achieve precise and efficient editing in cultured cells. Previously, we developed a platform capable of delivering CRISPR/Cas9 gRNAs and donor templates via adeno-associated virus to induce HDR (CASAAV-HDR).
View Article and Find Full Text PDFA Titin Missense Variant Causes Atrial Fibrillation.
medRxiv
December 2024
Division of Cardiology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA.
Rare and common genetic variants contribute to the risk of atrial fibrillation (AF). Although ion channels were among the first AF candidate genes identified, rare loss-of-function variants in structural genes such as have also been implicated in AF pathogenesis partly by the development of an atrial myopathy, but the underlying mechanisms are poorly understood. While truncating variants (tvs) have been causally linked to arrhythmia and cardiomyopathy syndromes, the role of missense variants (mvs) remains unclear.
View Article and Find Full Text PDFNovel FLNC variants in pediatric cardiomyopathy: an insight into disease mechanisms.
Hum Genomics
October 2024
Pediatric Research Institute, Children's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan, China.
Background: FLNC gene variants have predominantly been reported in adult populations with cardiomyopathies, and early-onset cases are less common. The genotype-phenotype relationship indicates that dilated cardiomyopathy (DCM) is often associated with FLNC truncating variants.
Methods: We conducted a comprehensive genetic analysis using next generation sequencing (NGS) to identify FLNC variants in patients with cardiovascular conditions.
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