Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction DOI Creative Commons
Jessika Iwanski, Christopher T. Pappas, Rachel M. Mayfield

et al.

npj Regenerative Medicine, Journal Year: 2024, Volume and Issue: 9(1)

Published: Sept. 16, 2024

Neonatal dilated cardiomyopathy (DCM) is a poorly understood muscular disease of the heart. Several homozygous biallelic variants in LMOD2, gene encoding actin-binding protein Leiomodin 2, have been identified to result severe DCM. Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting neonatal death. Thus, it evident that Lmod2 essential normal human muscle function. This study aimed understand underlying pathophysiology signaling pathways related first reported LMOD2 variant (c.1193 G > A, p.Trp398*). Using patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) mouse model harboring homologous mutation patient, we discovered dysregulated actin-thin filament lengths, altered contractility calcium handling properties, as well alterations serum response factor (SRF)-dependent pathway. These findings reveal may be regulating SRF activity an actin-dependent manner provide potential new strategy for development biologically active molecules target cardiomyopathies.

Language: Английский

Nonsense-Mediated mRNA Decay in Human Health and Diseases: Current Understanding, Regulatory Mechanisms and Future Perspectives DOI

Amrita Behera,

G. Panigrahi, Annapurna Sahoo

et al.

Molecular Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 12, 2024

Language: Английский

Citations

5
Interaction of cardiac leiomodin with the native cardiac thin filament DOI Creative Commons
Madison T. Little, Cristina M. Risi, Tania M. Larrinaga

et al.

PLoS Biology, Journal Year: 2025, Volume and Issue: 23(1), P. e3003027 - e3003027

Published: Jan. 30, 2025

Every heartbeat depends on cyclical contraction-relaxation produced by the interactions between myosin-containing thick and actin-based thin filaments (TFs) arranged into a crystalline-like lattice in cardiac sarcomere. Therefore, maintenance of filament length is crucial for myocardium function. The comprised an actin backbone, regulatory troponin complex tropomyosin that controls filaments. Thin controlled tropomodulin family proteins; caps pointed ends filaments, leiomodin (Lmod) promotes elongation “leaky-cap” mechanism. broader distribution Lmod implied to possibility its interaction with sides Here, we use biochemical structural approaches show (Lmod2) binds specific region native Ca 2+ -dependent manner. We demonstrate Lmod2’s unique C-terminal extension required binding backbone suggest assist localization surface propose Lmod2 regulates working protecting newly formed units during systole promoting polymerization at diastole.

Language: Английский

Citations

0
Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction DOI Creative Commons
Jessika Iwanski, Christopher T. Pappas, Rachel M. Mayfield

et al.

npj Regenerative Medicine, Journal Year: 2024, Volume and Issue: 9(1)

Published: Sept. 16, 2024

Neonatal dilated cardiomyopathy (DCM) is a poorly understood muscular disease of the heart. Several homozygous biallelic variants in LMOD2, gene encoding actin-binding protein Leiomodin 2, have been identified to result severe DCM. Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting neonatal death. Thus, it evident that Lmod2 essential normal human muscle function. This study aimed understand underlying pathophysiology signaling pathways related first reported LMOD2 variant (c.1193 G > A, p.Trp398*). Using patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) mouse model harboring homologous mutation patient, we discovered dysregulated actin-thin filament lengths, altered contractility calcium handling properties, as well alterations serum response factor (SRF)-dependent pathway. These findings reveal may be regulating SRF activity an actin-dependent manner provide potential new strategy for development biologically active molecules target cardiomyopathies.

Language: Английский

Citations

0