DCM associated LMNA mutations cause distortions in lamina structure and assembly

Bhattacharjee, Pritha; Dasgupta, Dipak; Sengupta, Kaushik

doi:10.1016/j.bbagen.2017.08.016

Cited by 19 publications

(30 citation statements)

References 50 publications

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“…For example, some of these genes link the cytoskeleton to the extracellular matrix (e.g., dystrophin [DMD], vinculin [VCL]), others link the cytoskeleton to the nucleus (e.g., nesprin-1 [SYNE1], lamin-A [LMNA], centromere protein F [CENP-F]), and others are mechanosensitive transcription factors (e.g., TAZ). Consistent with this idea, altered mechanobiology has been identified in DCM cells with mutations in the nonsarcomeric protein lamin A/C (82). Moreover, patients with mutations in these genes, such as those with Duchenne muscular dystrophy and Emery-Dreifuss muscular dystrophy, often develop DCM.…”

Section: Discussionmentioning

confidence: 75%

“…While the disease presentation in DCM depends on the exact mutation (80), we propose that disruption of mechanosensing in cardiomyocytes could be a common mechanism in the disease pathogenesis of other sarcomeric and nonsarcomeric DCM mutations. It has been proposed that DCM can be caused by molecular hypocontractility (4,76,81); however, there are also many DCMcausing mutations in nonsarcomeric genes with no known roles in contractility; suggesting that other mechanisms might be involved (1,3,82). Most of these genes are located along proposed mechanosensing pathways (83,84) used to sense and transduce mechanical forces.…”

Section: Discussionmentioning

confidence: 99%

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Disrupted mechanobiology links the molecular and cellular phenotypes in familial dilated cardiomyopathy

Clippinger

Cloonan

Greenberg

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a major indicator for heart transplant. The disease is frequently caused by mutations of sarcomeric proteins; however, it is not well understood how these molecular mutations lead to alterations in cellular organization and contractility. To address this critical gap in our knowledge, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, ΔK210. We determined the molecular mechanism of ΔK210 and used computational modeling to predict that the mutation should reduce the force per sarcomere. In mutant cardiomyocytes, we found that ΔK210 not only reduces contractility but also causes cellular hypertrophy and impairs cardiomyocytes’ ability to adapt to changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and disease). These results help link the molecular and cellular phenotypes and implicate alterations in mechanosensing as an important factor in the development of DCM.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Disrupted mechanobiology links the molecular and cellular phenotypes in familial dilated cardiomyopathy

Clippinger

Cloonan

Greenberg

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, some of these genes link the cytoskeleton to the extracellular matrix (e.g., dystrophin (DMD), vinculin (VCL)), others link the cytoskeleton to the nucleus (e.g., nesprin-1 (SYNE1), lamin-A (LMNA), centromere protein F (CENP-F)), and others are mechanosensitive transcription factors (e.g., TAZ). Consistent with this idea, altered mechanobiology has been identified in DCM cells with mutations in the non-sarcomeric protein lamin (82). Moreover, patients with mutations in these genes, such as those with Duchenne muscular dystrophy and Emery-Dreifuss muscular dystrophy, often develop DCM.…”

Section: Discussionmentioning

confidence: 77%

“…While the disease presentation in DCM depends on the exact mutation (79), we propose that disruption of mechanosensing could be a common mechanism in the disease pathogenesis of other sarcomeric and non-sarcomeric DCM mutations. It has been proposed that DCM can be caused by molecular hypocontractility (4, 80, 81); however, there are also many DCM-causing mutations in non-sarcomeric genes with no known roles in contractility; suggesting that other mechanisms might be involved (1, 3, 82). Most, but not all, of these genes are located along proposed mechanosensing pathways (83, 84) used to sense and transduce mechanical forces.…”

Section: Discussionmentioning

confidence: 99%

Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes in Familial Dilated Cardiomyopathy

Clippinger¹,

Cloonan²,

Greenberg³

et al. 2019

Preprint

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27Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a 28 major indicator for heart transplant. The disease is frequently caused by mutations of 29 sarcomeric proteins; however, it is not well understood how these molecular mutations 30 lead to alterations in cellular organization and contractility. To address this critical gap in 31 our knowledge, we studied the molecular and cellular consequences of a DCM mutation 32 in troponin-T, DK210. We determined the molecular mechanism of DK210 and used 33 computational modeling to predict that the mutation should reduce the force per 34 sarcomere. In mutant cardiomyocytes, we found that DK210 not only reduces contractility, 35 but also causes cellular hypertrophy and impairs cardiomyocytes' ability to adapt to 36 changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and 37 disease). These results link the molecular and cellular phenotypes and implicate 38 alterations in mechanosensing as an important factor in the development of DCM. 39Results 100 DK210 decreases calcium sensitivity in an in vitro motility assay 101We set out to decipher the molecular mechanism of the DK210 mutation in vitro. 102The molecular effects of cardiomyopathy mutations depend on the myosin isoform (7-9, 103 35-37) and therefore, we used porcine cardiac ventricular myosin (38). Porcine ventricular 104 cardiac myosin (MYH7) is 97% identical to human, while murine cardiac myosin (MYH6) 105 is only 92% identical. Porcine cardiac myosin has very similar biophysical properties to 106 human cardiac myosin, including the kinetics of the ATPase cycle, step size, and 107 sensitivity to load (38-41), making it an ideal myosin for biophysical studies. 108Given the role of troponin-T in thin filament regulation, we first determined whether 109 the DK210 mutation affects calcium-based regulation of myosin binding to thin filaments 110 using an in vitro motility assay (42). Reconstituted thin filaments, consisting of porcine 111 cardiac actin and recombinantly expressed human troponin and tropomyosin, were added 112 to a flow cell coated with porcine cardiac myosin in the presence of ATP. The speed of 113 filament translocation was measured as a function of added calcium. As has been 114 reported previously, the speed of regulated thin filament translocation increased 115 sigmoidally with increasing Ca 2+ concentration (43), ( Figure 1B). Data were fit with the Hill 116 equation to obtain the pCa50 (i.e., the concentration of calcium necessary for half-117 maximal activation). Consistent with previous studies using mouse cardiac, rabbit cardiac, 118 and rabbit skeletal muscle fibers (31, 33, 44), DK210 shows a right-shifted curve (pCa50 119 = 5.7 ± 0.1) compared to the WT (pCa50 = 6.1 ± 0.1; p < 0.0001), meaning more calcium 120 is needed for the same level of activation. This suggests that the mutant could show 121 impaired force production during a calcium transient. 122 7 123 Molecular mechanism of DK210-induced changes in thin filament regulat...

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“…Lamin B meshwork remains anchored predominantly to INM via the isoprenylation even during the mitosis [ 16 ]. Our group had showed previously that several mutants of lamin A bind to lamin B1 with differential stoichiometries and in these mutants, lamin B1 forms dilated meshwork [ 63 ]. Nevertheless, the influence on the lamin B network inside the nucleoplasm due to lamin A mutation is a little enigmatic.…”

Section: Importance Of Lamins Inside the Nucleoplasm And Their Role Imentioning

confidence: 99%

Nuclear filaments: role in chromosomal positioning and gene expression

Bera

Sengupta

2020

Nucleus

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Nuclear lamins form an elastic meshwork underlying the inner nuclear membrane and provide mechanical rigidity to the nucleus and maintain shape. Lamins also maintain chromosome positioning and play important roles in several nuclear processes like replication, DNA damage repair, transcription, and epigenetic modifications. LMNA mutations affect cardiac tissue, muscle tissues, adipose tissues to precipitate several diseases collectively termed as laminopathies. However, the rationale behind LMNA mutations and laminopathies continues to elude scientists. During interphase, several chromosomes form inter/intrachromosomal contacts inside nucleoplasm and several chromosomal loops also stretch out to make a ‘loop-cluster’ which are key players to regulate gene expressions. In this perspective, we have proposed that the lamin network in tandem with nuclear actin and myosin provide mechanical rigidity to the chromosomal contacts and facilitate loop-clusters movements. LMNA mutations thus might perturb the landscape of chromosomal contacts or loop-clusters positioning which can impair gene expression profile.

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DCM associated LMNA mutations cause distortions in lamina structure and assembly

Cited by 19 publications

References 50 publications

Disrupted mechanobiology links the molecular and cellular phenotypes in familial dilated cardiomyopathy

Disrupted mechanobiology links the molecular and cellular phenotypes in familial dilated cardiomyopathy

Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes in Familial Dilated Cardiomyopathy

Nuclear filaments: role in chromosomal positioning and gene expression

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