Special Issue "The New Frontier of Therapies for Nuclear Envelope and Lamin-Related Diseases: Selected Papers from 2019 International Meeting on Laminopathies"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: 30 June 2021.

Special Issue Editors

Dr. Giovanna Lattanzi
Website
Guest Editor
CNR Institute of Molecular Genetics, Unit of Bologna, Bologna, Italy
Interests: laminopathies; cell biology of lamins, emerin- and lamin-linked proteins; Emery-Dreifuss muscular dystrophy; Hutchinson–Gilford progeria syndrome (HGPS); mandibuloacral dysplasia; familial partial lipodystrophy type 2
Dr. Thomas Dechat
Website
Guest Editor
Ludwig Boltzmann Institute of Osteology, 1st Medical Department of Hanusch Hospital, Heinrich Collin Str. 30, A-1140 Vienna, Austria
Interests: nuclear lamins; LAP2alpha; nuclear structure; nuclear envelope disassembly and assembly; chromatin organization; cell cycle regulation; premature aging; osteogenesis
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Special Issue Information

Dear Colleagues,

This Special Issue will consist of selected papers from the 2019 International Meeting on Laminopathies on 2–5 September 2019 in London, UK. This is the 3rd edition of the International Meeting on Laminopathies, which is organized every other year in diverse European countries to gather scientists, clinicians, and patient organizations dealing with lamin research and laminopathies. This event is organized by the Italian Network for Laminopathies and by the French Network for Emery-Dreifuss muscular dystrophy and other nuclear envelope-related diseases. Previous meetings took place in Marseille (France) in 2015 and Bologna (Italy) in 2017. The 2019 edition has been organized as a joint meeting with the UK Nuclear Envelope and Chromatin Organization Meeting, organized by Qiuping Zhang and Kathy Shanahan at King’s College in London in collaboration with Eric Schirmer from the University of Edinburgh. Moreover, a satellite meeting of the European Network for Laminopathies has been scheduled on 3–5 September 2019 to allow cross-fertilization among European researchers, clinicians, patients, and their associations and to foster collaborations. This Special Issue of Cells will be focused on “The New Frontier of Therapies for Nuclear Envelope- and Lamin-Related Diseases”.

In this Special Issue, we aim to highlight approaches that exploit experimental work to identify therapeutic targets and test new therapeutic strategies, which we hope can provide a cure for laminopathies. This Special Issue thus offers the opportunity for attendees of the meeting to contribute and publish research findings and perspectives in this area.

Selected papers from the 2019 International Meeting on Laminopathies reporting on “The New Frontier of Therapies for Nuclear Envelope- and Lamin-Related Diseases” will be considered for publication. The papers submitted and selected for this Special Issue should neither have been previously published nor be under consideration for publication elsewhere and will be subject to a very rigorous peer-review process.

Dr. Giovanna Lattanzi
Dr. Thomas Dechat
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • lamin
  • nuclear envelope
  • laminopathies
  • therapies for laminopathies

Related Special Issue

Published Papers (5 papers)

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Research

Open AccessArticle
Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson–Gilford Progeria Syndrome with Ldlr Deficiency
Cells 2020, 9(10), 2252; https://doi.org/10.3390/cells9102252 - 08 Oct 2020
Abstract
Hutchinson–Gilford progeria syndrome (HGPS) is among the most devastating of the laminopathies, rare genetic diseases caused by mutations in genes encoding nuclear lamina proteins. HGPS patients age prematurely and die in adolescence, typically of atherosclerosis-associated complications. The mechanisms of HGPS-related atherosclerosis are not [...] Read more.
Hutchinson–Gilford progeria syndrome (HGPS) is among the most devastating of the laminopathies, rare genetic diseases caused by mutations in genes encoding nuclear lamina proteins. HGPS patients age prematurely and die in adolescence, typically of atherosclerosis-associated complications. The mechanisms of HGPS-related atherosclerosis are not fully understood due to the scarcity of patient-derived samples and the availability of only one atheroprone mouse model of the disease. Here, we generated a new atherosusceptible model of HGPS by crossing progeroid LmnaG609G/G609G mice, which carry a disease-causing mutation in the Lmna gene, with Ldlr−/− mice, a commonly used preclinical atherosclerosis model. Ldlr−/−LmnaG609G/G609G mice aged prematurely and had reduced body weight and survival. Compared with control mice, Ldlr−/−LmnaG609G/G609G mouse aortas showed a higher atherosclerosis burden and structural abnormalities typical of HGPS patients, including vascular smooth muscle cell depletion in the media, adventitial thickening, and elastin structure alterations. Atheromas of Ldlr−/−LmnaG609G/G609G mice had features of unstable plaques, including the presence of erythrocytes and iron deposits and reduced smooth muscle cell and collagen content. Ldlr−/−LmnaG609G/G609G mice faithfully recapitulate vascular features found in patients and thus provide a new tool for studying the mechanisms of HGPS-related atherosclerosis and for testing therapies. Full article
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Open AccessArticle
PCAF Involvement in Lamin A/C-HDAC2 Interplay during the Early Phase of Muscle Differentiation
Cells 2020, 9(7), 1735; https://doi.org/10.3390/cells9071735 - 20 Jul 2020
Abstract
Lamin A/C has been implicated in the epigenetic regulation of muscle gene expression through dynamic interaction with chromatin domains and epigenetic enzymes. We previously showed that lamin A/C interacts with histone deacetylase 2 (HDAC2). In this study, we deepened the relevance and regulation [...] Read more.
Lamin A/C has been implicated in the epigenetic regulation of muscle gene expression through dynamic interaction with chromatin domains and epigenetic enzymes. We previously showed that lamin A/C interacts with histone deacetylase 2 (HDAC2). In this study, we deepened the relevance and regulation of lamin A/C-HDAC2 interaction in human muscle cells. We present evidence that HDAC2 binding to lamin A/C is related to HDAC2 acetylation on lysine 75 and expression of p300-CBP associated factor (PCAF), an acetyltransferase known to acetylate HDAC2. Our findings show that lamin A and farnesylated prelamin A promote PCAF recruitment to the nuclear lamina and lamin A/C binding in human myoblasts committed to myogenic differentiation, while protein interaction is decreased in differentiating myotubes. Interestingly, PCAF translocation to the nuclear envelope, as well as lamin A/C-PCAF interaction, are reduced by transient expression of lamin A mutated forms causing Emery Dreifuss muscular dystrophy. Consistent with this observation, lamin A/C interaction with both PCAF and HDAC2 is significantly reduced in Emery–Dreifuss muscular dystrophy myoblasts. Overall, these results support the view that, by recruiting PCAF and HDAC2 in a molecular platform, lamin A/C might contribute to regulate their epigenetic activity required in the early phase of muscle differentiation. Full article
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Open AccessArticle
Consequences of Lmna Exon 4 Mutations in Myoblast Function
Cells 2020, 9(5), 1286; https://doi.org/10.3390/cells9051286 - 21 May 2020
Cited by 2
Abstract
Laminopathies are causally associated with mutations on the Lamin A/C gene (LMNA). To date, more than 400 mutations in LMNA have been reported in patients. These mutations are widely distributed throughout the entire gene and are associated with a wide range [...] Read more.
Laminopathies are causally associated with mutations on the Lamin A/C gene (LMNA). To date, more than 400 mutations in LMNA have been reported in patients. These mutations are widely distributed throughout the entire gene and are associated with a wide range of phenotypes. Unfortunately, little is known about the mechanisms underlying the effect of the majority of these mutations. This is the case of more than 40 mutations that are located at exon 4. Using CRISPR/Cas9 technology, we generated a collection of Lmna exon 4 mutants in mouse C2C12 myoblasts. These cell models included different types of exon 4 deletions and the presence of R249W mutation, one of the human variants associated with a severe type of laminopathy, LMNA-associated congenital muscular dystrophy (L-CMD). We characterized these clones by measuring their nuclear circularity, myogenic differentiation capacity in 2D and 3D conditions, DNA damage, and levels of p-ERK and p-AKT (phosphorylated Mitogen-Activated Protein Kinase 1/3 and AKT serine/threonine kinase 1). Our results indicated that Lmna exon 4 mutants showed abnormal nuclear morphology. In addition, levels and/or subcellular localization of different members of the lamin and LINC (LInker of Nucleoskeleton and Cytoskeleton) complex were altered in all these mutants. Whereas no significant differences were observed for ERK and AKT activities, the accumulation of DNA damage was associated to the Lmna p.R249W mutant myoblasts. Finally, significant myogenic differentiation defects were detected in the Lmna exon 4 mutants. These results have key implications in the development of future therapeutic strategies for the treatment of laminopathies. Full article
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Open AccessArticle
Lamin A/C Assembly Defects in LMNA-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy
Cells 2020, 9(4), 844; https://doi.org/10.3390/cells9040844 - 31 Mar 2020
Cited by 4
Abstract
LMNA encodes for Lamin A/C, type V intermediate filaments that polymerize under the inner nuclear membrane to form the nuclear lamina. A small fraction of Lamin A/C, less polymerized, is also found in the nucleoplasm. Lamin A/C functions include roles in nuclear resistance [...] Read more.
LMNA encodes for Lamin A/C, type V intermediate filaments that polymerize under the inner nuclear membrane to form the nuclear lamina. A small fraction of Lamin A/C, less polymerized, is also found in the nucleoplasm. Lamin A/C functions include roles in nuclear resistance to mechanical stress and gene regulation. LMNA mutations are responsible for a wide variety of pathologies, including Emery–Dreifuss (EDMD) and LMNA-related congenital muscular dystrophies (L-CMD) without clear genotype–phenotype correlations. Both diseases presented with striated muscle disorders although L-CMD symptoms appear much earlier and are more severe. Seeking for pathomechanical differences to explain the severity of L-CMD mutations, we performed an in silico analysis of the UMD-LMNA database and found that L-CMD mutations mainly affect residues involved in Lamin dimer and tetramer stability. In line with this, we found increased nucleoplasmic Lamin A/C in L-CMD patient fibroblasts and mouse myoblasts compared to the control and EDMD. L-CMD myoblasts show differentiation defects linked to their inability to upregulate muscle specific nuclear envelope (NE) proteins expression. NE proteins were mislocalized, leading to misshapen nuclei. We conclude that these defects are due to both the absence of Lamin A/C from the nuclear lamina and its maintenance in the nucleoplasm of myotubes. Full article
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Open AccessArticle
Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice
Cells 2020, 9(3), 765; https://doi.org/10.3390/cells9030765 - 20 Mar 2020
Abstract
Variants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report [...] Read more.
Variants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report unexpected cardiovascular phenotypes in patients with LMNA-associated lipodystrophies, illustrating the complex multitissular pathophysiology of the disease and the need for specific cardiovascular investigations in affected patients. A 33-year-old woman was diagnosed with generalized lipodystrophy and atypical progeroid syndrome due to the newly identified heterozygous LMNA p.(Asp136Val) variant. Her complex cardiovascular phenotype was associated with atherosclerosis, aortic valvular disease and left ventricular hypertrophy with rhythm and conduction defects. A 29-year-old woman presented with a partial lipodystrophy syndrome and a severe coronary atherosclerosis which required a triple coronary artery bypass grafting. She carried the novel heterozygous p.(Arg60Pro) LMNA variant inherited from her mother, affected with partial lipodystrophy and dilated cardiomyopathy. Different lipodystrophy-associated LMNA pathogenic variants could target cardiac vasculature and/or muscle, leading to complex overlapping phenotypes. Unifying pathophysiological hypotheses should be explored in several cell models including adipocytes, cardiomyocytes and vascular cells. Patients with LMNA-associated lipodystrophy should be systematically investigated with 24-h ECG monitoring, echocardiography and non-invasive coronary function testing. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Aggravation of atherosclerosis in Ldlr-KO mice with ubiquitous progerin expression
Authors: Vicente Andrès
Affiliation: Laboratory of Molecular and Genetic Cardiovascular Pathophysiology Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) Melchor Fernández Almagro 3, 28029 Madrid (Spain)

Title: Nuclear pore complexes cluster in dysmorphic nuclei of normal and progeria cells during replicative senescence
Authors: Jennifer Röhrl; Karima Djabali
Affiliation: Epigenetics of Aging, Department of Dermatology and Allergy, TUM school of Medicine, Technical University of Munich (TUM), 85748 Garching, Germany.

Title: Heart involvement in laminopathies: an updated overview from pathophysiology to arrhythmic risk stratification and recent advances in clinical management
Authors: Cinzia Forleo 1, Roberta Ruggieri 1, Aldo Agea 1, Sandro Sorrentino 1, Andrea Igoren Guaricci 1, Francesco Loizzi 1, Maria Cristina Carella 1, Miriam Albanese 1, Mara Piccolo 1, Paolo Pollice 1, Bagnu
Affiliation: 1 Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy 2 Division of Medical Genetics, Department of Biomedial Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy 3 Interdisciplinary Department of Medicine, Section of Radiology, University of Bari Aldo Moro, Bari, Italy
Abstract: Since 1999 Bonne’s discover of the first mutation in the Lamin A/C gene (LMNA), an increasing number of mutations have been associated with a wide spectrum of human diseases, overall referred to as laminopathies, characterized by large phenotypic heterogeneity, encompassing cardiac, neuromuscular, metabolic disorders and premature aging syndromes. Heart and skeletal muscles are the most affected systems, accounting for about 80% of total LMNA mutations. The cardiac phenotypes of laminopathies are frequently gathered in complex not mutually exclusive clinical patterns and may include electrical disturbances (conduction system defects, supraventricular, and ventricular arrhythmias) and structural abnormalities (mainly left ventricular dysfunction and dilated cardiomyopathy, but also left ventricular non-compaction, arrhythmogenic right ventricular, hypertrophic and, more recently, restrictive cardiomyopathies). The clinical evolution of cardiac laminopathies is variable, representing sudden cardiac death, progression to end-stage heart failure needing heart transplantation, and thromboembolic events the most severe complications. The poor prognosis requires suitable risk stratification. This review aims to explore LMNA-related cardiac phenotypes and to give an update concerning the risk stratification of sudden cardiac death in cardiolaminopathies. We also attempt to summarize LMNA-related altered signaling pathways leading to cardiac laminopathies, and to evaluate current and future therapies in LMNA mutation carriers.

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