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      Current insights into LMNA cardiomyopathies: Existing models and missing LINCs

      review-article
      Author(s): ,
      Publication date (Electronic):
      Journal: Nucleus
      Publisher: Taylor & Francis
      Keywords: cardiomyocyte, cardiomyopathy, LINC complex, LMNA, mechanotransduction, nuclear lamina, prelamin A

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          ABSTRACT

          The nuclear lamina is a critical structural domain for the maintenance of genomic stability and whole-cell mechanics. Mutations in the LMNA gene, which encodes nuclear A-type lamins lead to the disruption of these key cellular functions, resulting in a number of devastating diseases known as laminopathies. Cardiomyopathy is a common laminopathy and is highly penetrant with poor prognosis. To date, cell mechanical instability and dysregulation of gene expression have been proposed as the main mechanisms driving cardiac dysfunction, and indeed discoveries in these areas have provided some promising leads in terms of therapeutics. However, important questions remain unanswered regarding the role of lamin A dysfunction in the heart, including a potential role for the toxicity of lamin A precursors in LMNA cardiomyopathy, which has yet to be rigorously investigated.

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          Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.

          Pascale Richard, Philippe Charron, Lucie Carrier … (2003)
          Hypertrophic cardiomyopathy is an autosomal-dominant disorder in which 10 genes and numerous mutations have been reported. The aim of the present study was to perform a systematic screening of these genes in a large population, to evaluate the distribution of the disease genes, and to determine the best molecular strategy in clinical practice. The entire coding sequences of 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC, andTNNC1) were analyzed in 197 unrelated index cases with familial or sporadic hypertrophic cardiomyopathy. Disease-causing mutations were identified in 124 index patients ( approximately 63%), and 97 different mutations, including 60 novel ones, were identified. The cardiac myosin-binding protein C (MYBPC3) and beta-myosin heavy chain (MYH7) genes accounted for 82% of families with identified mutations (42% and 40%, respectively). Distribution of the genes varied according to the prognosis (P=0.036). Moreover, a mutation was found in 15 of 25 index cases with "sporadic" hypertrophic cardiomyopathy (60%). Finally, 6 families had patients with more than one mutation, and phenotype analyses suggested a gene dose effect in these compound-heterozygous, double-heterozygous, or homozygous patients. These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testing MYBPC3 and MYH7 and then focus on TNNI3, TNNT2, and MYL2. Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened.
          Article 0 comments Cited 224 times – based on 0 reviews     Review now
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            Genomic instability in laminopathy-based premature aging.

            Baohua Liu, Jianming Wang, Kui Ming Chan … (2005)
            Premature aging syndromes often result from mutations in nuclear proteins involved in the maintenance of genomic integrity. Lamin A is a major component of the nuclear lamina and nuclear skeleton. Truncation in lamin A causes Hutchinson-Gilford progerial syndrome (HGPS), a severe form of early-onset premature aging. Lack of functional Zmpste24, a metalloproteinase responsible for the maturation of prelamin A, also results in progeroid phenotypes in mice and humans. We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents. Bone marrow cells isolated from Zmpste24-/- mice show increased aneuploidy and the mice are more sensitive to DNA-damaging agents. Recruitment of p53 binding protein 1 (53BP1) and Rad51 to sites of DNA lesion is impaired in Zmpste24-/- MEFs and in HGPS fibroblasts, resulting in delayed checkpoint response and defective DNA repair. Wild-type MEFs ectopically expressing unprocessible prelamin A show similar defects in checkpoint response and DNA repair. Our results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging.
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              Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy.

              Eduardo Garcia-Gras, Raffaella Lombardi, Michael J Giocondo … (2006)
              Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic disease caused by mutations in desmosomal proteins. The phenotypic hallmark of ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique phenotype with a yet-to-be-defined molecular mechanism. We established atrial myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for human ARVC. We show suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/beta-catenin signaling through Tcf/Lef1 transcription factors. The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets. We further show that cardiac-restricted deletion of Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic lethality in the homozygous state. Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC. We believe our results provide for a novel molecular mechanism for the pathogenesis of ARVC and establish cardiac-restricted DP-deficient mice as a model for human ARVC. These findings could provide for the opportunity to identify new diagnostic markers and therapeutic targets in patients with ARVC.
              Article 0 comments Cited 184 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nucleus
                Journal ID (iso-abbrev): Nucleus
                Journal ID (publisher-id): KNCL
                Journal ID (publisher-id): kncl20
                Title: Nucleus
                Publisher: Taylor & Francis
                ISSN (Print): 1949-1034
                ISSN (Electronic): 1949-1042
                Publication date Collection: 2017
                Publication date (Electronic): 26 January 2017
                Publication date PMC-release: 26 January 2017
                Volume: 8
                Issue: 1 , SEB Brighton 2016: Dynamic Organization of the Nucleus, Pt. 1 of 2
                Pages: 17-33
                Affiliations
                King's College London, The James Black Centre , London, United Kingdom
                Author notes
                CONTACT Catherine Shanahan, Email: cathy.shanahan@ 123456kcl.ac.uk ; King's College London, The James Black Centre , 125 Coldharbour Lane, London SE5 9NU, United Kingdom.

                Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/kncl.

                Article
                Publisher ID: 1260798
                DOI: 10.1080/19491034.2016.1260798
                PMC ID: 5287098
                PubMed ID: 28125396
                SO-VID: 11805551-858e-4703-ab8b-f13d47a17761
                Copyright © © 2017 The Author(s). Published with license by Taylor & Francis
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

                History
                Date received : 30 September 2016
                Date revision received : 4 November 2016
                Date accepted : 10 November 2016
                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 134, Pages: 17
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: cardiomyocyte,cardiomyopathy,linc complex,lmna,mechanotransduction,nuclear lamina,prelamin a
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: cardiomyocyte, cardiomyopathy, linc complex, lmna, mechanotransduction, nuclear lamina, prelamin a

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