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Lamins are inner nuclear membrane proteins that belong to the intermediate filament family. Lamin A/C lie adjacent to the heterochromatin structure in polymer form, providing skeletal to the nucleus. Based on the localization, lamin A/C provides nuclear stability and cytoskeleton to the nucleus and modulates chromatin organization and gene expression. Besides being the structural protein making the inner nuclear membrane in polymer form, lamin A/C functions as a signalling molecule involved in gene expression as an enhancer inside the nucleus. Lamin A/C regulates various cellular pathways like autophagy and energy balance in the cytoplasm. Its expression is highly variable in differentiated tissues, higher in hard tissues like bone and muscle cells, and lower in soft tissues like the liver and brain. In muscle cells, including the heart, lamin A/C must be expressed in a balanced state. Lamin A/C mutation is linked with various diseases, such as muscular dystrophy, lipodystrophy, and cardiomyopathies. It has been observed that a good number of mutations in the LMNA gene impact cardiac activity and its function. Although several works have been published, there are still several unexplored areas left regarding the lamin A/C function and structure in the cardiovascular system and its pathological state. In this review, we focus on the structural organization, expression pattern, and function of lamin A/C, its interacting partners, and the pathophysiology associated with mutations in the lamin A/C gene, with special emphasis on cardiovascular diseases. With the recent finding on lamin A/C, we have summarized the possible therapeutic interventions to treat cardiovascular symptoms and reverse the molecular changes., Competing Interests: Declaration of competing interest The authors declare that there are no further conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

LMNA-related muscular dystrophy is a major disease phenotype causing mortality and morbidity in laminopathies, but its pathogenesis is still unclear. To explore the molecular pathogenesis, a knock-in mouse harbouring the Lmna-W520R mutation was modelled. Morphological and motor functional analyses showed that homozygous mutant mice revealed severe muscular atrophy, profound motor dysfunction, and shortened lifespan, while heterozygotes showed a variant arrangement of muscle bundles and mildly reduced motor capacity. Mechanistically, the FOXO1/GADD45A pathway involving muscle atrophy processes was found to be altered in vitro and in vivo assays. The expression levels of FOXO1 and its downstream regulatory molecule GADD45A significantly increased in atrophic muscle tissue. The elevated expression of FOXO1 was associated with decreased H3K27me3 in its gene promotor region. Overexpression of GADD45A induced apoptosis and cell cycle arrest of myoblasts in vitro, and it could be partially restored by the FOXO1 inhibitor AS1842856, which also slowed the muscle atrophy process with improved motor function and prolonged survival time of homozygous mutant mice in vivo. Notably, the inhibitor also partly rescued the apoptosis and cell cycle arrest of hiPSC-derived myoblasts harbouring the LMNA-W520R mutation. Together, these data suggest that the activation of the FOXO1/GADD45A pathway contributes to the pathogenesis of LMNA-related muscle atrophy, and it might serve as a potential therapeutic target for laminopathies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

We investigated the role of LMNA in adipose tissue by developing a novel mouse model of lipodystrophy. Transgenic mice were generated that express the LMNA mutation that causes familial partial lipodystrophy of the Dunnigan type (FPLD2). The phenotype observed in FPLD-transgenic mice resembles many of the features of human FPLD2, including lack of fat accumulation, insulin resistance, and enlarged, fatty liver. Similar to the human disease, FPLD-transgenic mice appear to develop normally, but after several weeks they are unable to accumulate fat to the same extent as their wild-type littermates. One poorly understood aspect of lipodystrophies is the mechanism of fat loss. To this end, we have examined the effects of the FPLD2 mutation on fat cell function. Contrary to the current literature, which suggests FPLD2 results in a loss of fat, we found that the key mechanism contributing to the lack of fat accumulation involves not a loss, but an apparent inability of the adipose tissue to renew itself. Specifically, preadipocytes are unable to differentiate into mature and fully functional adipocytes. These findings provide insights not only for the treatment of lipodystrophies, but also for the study of adipogenesis, obesity, and insulin resistance.

Background: The literature on laminopathy with ventricular phenotype is extensive. However, the pathogenicity of LMNA variations in atrial lesions still lacks research., Objective: The purpose of this study was to characterize the atrial phenotypes and possible mechanisms in a large Chinese family with heart-hand syndrome carrying a LMNA missense variant in rod 2B domain (c.1003C>T p.R335W)., Methods: Clinical characteristics were collected on the basis of the pedigree investigation. Comprehensive functional analyses, including molecular dynamic (MD) simulation, cellular, and animal functional assays, determined the pathogenicity in atrial myopathy., Results: In the pedigree investigation, 6 of 13 of the mutation carriers showed heterogeneous cardiac phenotypes and 8 carriers also had brachydactyly. In silico molecular dynamics simulations predicted increased binding energy of the R335W mutant lamin A. Atrial cardiomyocytes (HL-1, human induced pluripotent stem cell-derived atrial cardiomyocytes) expressing R335W showed abnormal nuclear morphology, compromised DNA repair, and dysfunctional contraction. Adult zebrafish expressing mutant lamin A showed increased P wave duration in the electrocardiogram, decreased peak A wave velocity in echocardiography, and atrial lesions under the transmission electron microscope., Conclusion: LMNA p.R335W mutation leads to familial heart-hand syndrome characterized by an overlapping phenotype of prominent atrial lesions and brachydactyly. The unstable lamin dimerization and impaired DNA repair are possible mechanisms underlying cardiac phenotypes. Our findings consolidated the genetic role in the course of atrial arrhythmias and cardiac aging, which is helpful in the diagnosis and treatment of cardiac laminopathy., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

LAMIN A/C, encoded by the LMNA gene, supports the normal structure of the cell nucleus and regulates the connection between the nucleus and the cytoskeleton as a component of the nucleus envelope. The loss of expression and function of the LMNA gene would lead to the occurrence of congenital muscular dystrophy and Emery-Dreifuss muscular dystrophy which are collectively named as laminopathies. Here, we report a human induced pluripotent stem cell (iPSC) line (EHTJUi005-A-3) generated from a wild iPSC (EHTJUi005-A) with homozygous knockout of the gene LMNA through CRISPR/Cas9. This iPSC line provides a useful research model for studying laminopathies disease., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Lamins are the major component of nuclear lamina, maintaining structural integrity of the nucleus. Lamin A/C variants are well established to cause a spectrum of disorders ranging from myopathies to progeria, termed laminopathies. Phenotypes resulting from variants in LMNB1 and LMNB2 have been much less clearly defined., Methods: We investigated exome and genome sequencing from the Deciphering Developmental Disorders Study and the 100,000 Genomes Project to identify novel microcephaly genes., Results: Starting from a cohort of patients with extreme microcephaly, 13 individuals with heterozygous variants in the two human B-type lamins were identified. Recurrent variants were established to be de novo in nine cases and shown to affect highly conserved residues within the lamin ɑ-helical rod domain, likely disrupting interactions required for higher-order assembly of lamin filaments., Conclusion: We identify dominant pathogenic variants in LMNB1 and LMNB2 as a genetic cause of primary microcephaly, implicating a major structural component of the nuclear envelope in its etiology and defining a new form of laminopathy. The distinct nature of this lamin B-associated phenotype highlights the strikingly different developmental requirements for lamin paralogs and suggests a novel mechanism for primary microcephaly warranting future investigation.

The eukaryotic genome inside the nucleus is enveloped by two membranes, the Outer Nuclear Membrane (ONM) and the Inner Nuclear Membrane (INM). Tethered to the INM is the nuclear lamina, a fibrillar network composed of lamins-the nuclear intermediate filaments, and membrane associated proteins. The nuclear lamina interacts with several nuclear structures, including chromatin. As most nuclear functions, including regulation of gene expression, chromosome segregation and duplication as well as nuclear structure, are highly conserved in metazoans, the Caenorhabditis elegans nematode serves as a powerful model organism to study nuclear processes and architecture. This translucent organism can easily be observed under a microscope as a live embryo, larvae and even adult. Here we will review the data on nuclear lamina composition and functions gathered from studies using C. elegans model organisms: We will discuss genome spatial organization and its contribution to gene expression. We will review both the interaction between the cytoplasm and the nucleus and mechanotransduction mechanism. Finally, we will discuss disease causing mutation in nuclear lamins, including the use of this animal model in diseases research., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mutations in LMNA gene are known to cause a broad range of diseases called laminopathies. We have generated two induced pluripotent stem cell lines FAMRCi006-A and FAMRCi006-B from a patient carrying LMNA p. p.Arg527Pro mutation associated with Emery-Dreifuss muscular dystrophy and dilated cardiomyopathy. Patient-specific peripheral blood mononuclear cells were reprogrammed to iPSCs using Sendai virus reprogramming system. Characterization of iPSCs had revealed pluripotency marker expression, normal karyotype, ability to differentiate into three embryonic germ layers. The reported iPSC lines could be a useful tool for in vitro modeling of laminopathies associated with LMNA genetic variants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

The occurrence of cardiovascular diseases increases with age independent of other risk factors, and the percentage of senescent cells is significantly elevated in vascular cells at atherosclerotic sites. Patients with accelerated aging syndromes caused by mutant lamin A protein, a structural component in nuclear lamina, also share many similarities with normal aged people, including the propensity to develop atherosclerosis. Recent studies have revealed the accumulation of prelamin A in normal aged vascular cells, and that lamin A participated as a mechanosensitive molecule in regulating various cellular events. These findings suggest that the ectopic expression of mutant lamin A or lamin A precursor (prelamin A) not only causes defects in cell mechanics, but it also disturbs stress-induced mechanotransduction pathways involving lamin A, both of which may contribute to vascular dysregulation. This review summarizes the current understanding of how lamin proteins are involved in vascular cell during aging, with a particular focus on the effect of mechanical stresses from blood flow on nuclear lamina of endothelial cells. Related studies are clarifying the role of lamin A in the progression of atherosclerosis, which will aid in the development of potential therapies for those suffering from lamin A-associated accelerated aging syndromes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Heterochromatin protein 1 (HP1) isoforms are conserved non-histone chromatin-binding proteins that play an important role in packaging of heterochromatin and gene regulation. The functions of HP1 isoforms α and β are influenced by the nuclear lamins. Cells expressing disease-causing lamin A rod domain mutants show depletion of HP1α and β and E3 ubiquitin ligase HECW2 is upregulated in these cells. However, the role of HECW2 in the turnover of HP1 proteins has been hitherto unexplored. Here, we show that HECW2 interacts with HP1 isoforms α and β but not HP1γ. Ectopic expression of HECW2 causes the ubiquitination of HP1α and β, thereby targeting them for proteasomal degradation. Downregulation of HECW2 increases their steady-state levels indicating its role in their homeostatic regulation. Our results give important insights into the mechanism of proteasomal degradation of HP1 proteins in laminopathic cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Lamins constitute the major architectural proteins of the nuclear lamina that help in maintaining nuclear organization. Mutations in lamins are associated with diverse degenerative diseases, collectively termed laminopathies. HECW2, a HECT-type E3 ubiquitin ligase, is transcriptionally upregulated in HeLa cells expressing Emery-Dreifuss muscular dystrophy-causing-lamin A mutants. However, the role of HECW2 upregulation in mediating downstream effects in lamin mutant-expressing cells was previously unexplored. Here, we show that HECW2 interacts with two lamin A-binding proteins, proliferating cell nuclear antigen (PCNA), via a canonical PCNA-interacting protein (PIP) motif, and lamin B1. HECW2 mediates their ubiquitination and targets them for proteasomal degradation. Cells expressing lamin A mutants G232E and Q294P, in which HECW2 is upregulated, show increased proteasomal degradation of PCNA and lamin B1 most likely mediated by HECW2. Our findings establish HECW2 as an E3 ubiquitin ligase for PCNA and lamin B1 which regulates their levels in laminopathic cells. We also found that HECW2 interacts with wild-type lamin A and ubiquitinates it and this interaction is reduced in case of lamin mutants G232E and Q294P. Our findings suggest that interplay among HECW2, lamin A, PCNA, and lamin B1 determines their respective homeostatic levels in the cell and dysregulation of these interactions may contribute to the pathogenicity of laminopathies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cystic Fibrosis (CF) is a recessively inherited disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR has a pivotal role in the onset of CF, and several proteins are involved in its homeostasis. To study CFTR interactors at protein species level, we used a functional proteomics approach combining 2D-DIGE, mass spectrometry and enrichment analysis. A human bronchial epithelial cell line with cystic fibrosis (CFBE41o-) and the control (16HBE14o-) were used for the comparison. 73 differentially abundant spots were identified and some validated by western-blot. Enrichment analysis highlighted molecular pathways in which ezrin, HSP70, endoplasmin and lamin A/C, in addition to CFTR, were considered central hubs in CFTR homeostasis. These proteins acquire different functions through post-translational modifications, emphasizing the importance of studying the CF proteome at protein species level. Moreover, serpin H1, prelamin A/C, protein-SET and cystatin-B were associated to CF, demonstrating the importance of heat shock response, cross-talk between the cytoskeleton and signal transduction, chronic inflammation and alteration of CFTR gating in the pathophysiology of the disease. These results open new perspectives for the understanding of the proteostasis network, characteristic of CF pathology, and could provide a springboard for new therapeutic strategies., Biological Significance: Homeostasis of CFTR is a dynamic process managed by multiple proteostatic pathways. The used gel-based proteomic approach and enrichment analysis pointed out protein species variations among Human Bronchial (16HBE14o-) and Cystic Fibrosis Bronchial Epithelial cell lines (CFBE41o-) and specific molecular mechanisms involved in CF. In particular, we have highlighted HSP70 (HSP7C), HSP90 (endoplasmin), ERM proteins (ezrin), and lamin-A/C as central hubs of the functional analysis. Moreover, for the first time we consider serpin H1, lamin A/C, protein-SET and cystatin-B important player in CF, affecting acute exacerbation, cytoskeleton reorganization, CFTR gating and chronic inflammation in CF. Due to the presence of different spots corresponding to the same protein, we focalize our attention on the idea that a "protein species discourse" is mandatory to well-define functional roles of proteins. Our approach has permitted to pay attention to the molecular mechanisms which regulate pathways directly or indirectly involved with CFTR defects: heat shock response, cross-talk between cytoskeleton and signal transduction, chronic inflammation and alteration of CFTR gating. Our data could open new perspectives into the understanding of CF, identifying potential targets for drug treatments in order to alleviate Δ508CFTR membrane instability and consequently increase life expectancy for CF patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Laminopathies (diseases related to A/C mutations of lamines) are rare genetic diseases with an extensive phenotypic spectrum, including lipodystrophic syndromes-characterized by a selective loss of adipose tissue-of which the partial Dunnigan family type is the most frequent., Case Report: We report on a 55-year-old woman with diabetes and long-term disabling myalgia. Her cushingoid morphotype, associated with cutaneous lipo-atrophy and muscle hypertrophy in addition to a genetic heritage, led us to the diagnosis of complex partial familial lipodystrophy heterozygous LMNA_c.82C>T, p.Arg28Trp mutation., Conclusion: Familial partial lipodystrophic syndromes may have varied phenotypes, mainly cardio-metabolic, which could mimic a particularly severe type 2 diabetes. The diagnostic work-up of this disease has to include a careful investigation of gait troubles and paroxysmal conduction that could lead to sudden death, as well as a genetic examination. In some cases, recombinant leptin can be proposed., (Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Nuclear size is generally maintained within a defined range in a given cell type. Changes in cell size that occur during cell growth, development, and differentiation are accompanied by dynamic nuclear size adjustments in order to establish appropriate nuclear-to-cytoplasmic volume relationships. It has long been recognized that aberrations in nuclear size are associated with certain disease states, most notably cancer. Nuclear size and morphology must impact nuclear and cellular functions. Understanding these functional implications requires an understanding of the mechanisms that control nuclear size. In this review, we first provide a general overview of the diverse cellular structures and activities that contribute to nuclear size control, including structural components of the nucleus, effects of DNA amount and chromatin compaction, signaling, and transport pathways that impinge on the nucleus, extranuclear structures, and cell cycle state. We then detail some of the key mechanistic findings about nuclear size regulation that have been gleaned from a variety of model organisms. Lastly, we review studies that have implicated nuclear size in the regulation of cell and nuclear function and speculate on the potential functional significance of nuclear size in chromatin organization, gene expression, nuclear mechanics, and disease. With many fundamental cell biological questions remaining to be answered, the field of nuclear size regulation is still wide open., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Lamins are structural components of the nuclear lamina and integral parts of the nucleoplasm. The tripartite domain structure partitions the molecule into an amino-terminal head, central rod and a carboxy-terminal tail domain. The tail domain contains a nuclear localization sequence and in most lamins an additional CaaX motif, which is necessary to post-translationally process prelamin to mature lamin. As players of nuclear and cellular integrity, lamins must possess unrestrained access to the nucleus. To study whether nuclear trafficking of lamins is compromised in laminopathies, we determined relative nuclear import activities between expressed prelamin A and selected laminopathy-inducing mutants thereof. Furthermore, the impact of inhibition of maturation on nuclear import of expressed prelamin A was examined. To perform quantitative transport measurements, import competent but lamina incorporation-deficient GFP- or DsRed-tagged prelamin A deletion mutants were used, which lacked the head and rod domain (ΔHR-prelamin A). Nuclear accumulation of ΔHR-prelamin A carrying the lipodystrophy and metabolic syndrome-inducing mutations R419C and L421P or progeria-causing deletions was significantly reduced, but that of the maturation-deficient mutant ΔHR-prelamin A SSIM was significantly increased. In the case of the full length prelamin A mutants R419C and L421P altered subcellular localization and reduced lamina incorporation were detected, with the prelamin A-binding protein Narf being redistributed into R419-containing aggregates. The results suggest that impaired nuclear transport of certain prelamin A mutants may represent a contributing factor in the pathogenesis of certain laminopathies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In eukaryotes, the function of the cell's nucleus has primarily been considered to be the repository for the organism's genome. However, this rather simplistic view is undergoing a major shift, as it is increasingly apparent that the nucleus has functions extending beyond being a mere genome container. Recent findings have revealed that the structural composition of the nucleus changes during development and that many of these components exhibit cell- and tissue-specific differences. Increasing evidence is pointing to the nucleus being integral to the function of the interphase cytoskeleton, with changes to nuclear structural proteins having ramifications affecting cytoskeletal organization and the cell's interactions with the extracellular environment. Many of these functions originate at the nuclear periphery, comprising the nuclear envelope (NE) and underlying lamina. Together, they may act as a "hub" in integrating cellular functions including chromatin organization, transcriptional regulation, mechanosignaling, cytoskeletal organization, and signaling pathways. Interest in such an integral role has been largely stimulated by the discovery that many diseases and anomalies are caused by defects in proteins of the NE/lamina, the nuclear envelopathies, many of which, though rare, are providing insights into their more common variants that are some of the major issues of the twenty-first century public health. Here, we review the contributions that mouse mutants have made to our current understanding of the NE/lamina, their respective roles in disease and the use of mice in developing potential therapies for treating the diseases., (© 2014 Elsevier Inc. All rights reserved.)

Extensive efforts have been devoted to study A-type lamins because mutations in their gene, LMNA in humans, are associated with a number of diseases. The mouse germline mutations in the A-type lamins (encoded by Lmna) exhibit postnatal lethality at either 4-8 postnatal (P) weeks or P16-18 days, depending on the deletion alleles. These mice exhibit defects in several tissues including hearts and skeletal muscles. Despite numerous studies, how the germline mutation of Lmna, which is expressed in many postnatal tissues, affects only selected tissues remains poorly understood. Addressing the tissue specific functions of Lmna requires the generation and careful characterization of conditional Lmna null alleles. Here we report the creation of a conditional Lmna knockout allele in mice by introducing loxP sites flanking the second exon of Lmna. The Lmna(flox/flox) mice are phenotypically normal and fertile. We show that Lmna homozygous mutants (Lmna(Δ/Δ)) generated by germline Cre expression display postnatal lethality at P16-18 days with defects similar to a recently reported germline Lmna knockout mouse that exhibits the earliest lethality compared to other germline knockout alleles. This conditional knockout mouse strain should serve as an important genetic tool to study the tissue specific roles of Lmna, which would contribute toward the understanding of various human diseases associated with A-type lamins., (Copyright © 2013 Elsevier Inc. All rights reserved.)