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      The structural and gene expression hypotheses in laminopathic diseases—not so different after all

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          Abstract

          Laminopathies are a diverse group of rare diseases with various pathologies in different tissues, which are linked to mutations in the LMNA gene. Historically, the structural disease model proposed mechanical defects of the lamina and nuclear fragility, the gene expression model impairment of spatial chromatin organization and signaling pathways as underlying mechanisms leading to the pathologies. Exciting findings in the past few years showing that mechanical forces are directly transmitted into the nucleus, where they affect chromatin organization and mechanoresponsive signaling molecules, have led to a revised concept of an integrative unified disease model, in which lamin-mediated pathways in mechanotransduction and chromatin regulation are highly interconnected and mutually dependent. In this Perspective we highlight breakthrough findings providing new insight into lamin-linked mechanisms of mechanotransduction and chromatin regulation and discuss how a combined and interrelated impairment of these functions by LMNA mutations may impair the complex mechanosignaling network and cause tissue-specific pathologies in laminopathies.

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          Most cited references 49

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          Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation.

          Tissues can be soft like fat, which bears little stress, or stiff like bone, which sustains high stress, but whether there is a systematic relationship between tissue mechanics and differentiation is unknown. Here, proteomics analyses revealed that levels of the nucleoskeletal protein lamin-A scaled with tissue elasticity, E, as did levels of collagens in the extracellular matrix that determine E. Stem cell differentiation into fat on soft matrix was enhanced by low lamin-A levels, whereas differentiation into bone on stiff matrix was enhanced by high lamin-A levels. Matrix stiffness directly influenced lamin-A protein levels, and, although lamin-A transcription was regulated by the vitamin A/retinoic acid (RA) pathway with broad roles in development, nuclear entry of RA receptors was modulated by lamin-A protein. Tissue stiffness and stress thus increase lamin-A levels, which stabilize the nucleus while also contributing to lineage determination.
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            Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.

            Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and a cardiomyopathy with conduction blocks which is life-threatening. Two modes of inheritance exist, X-linked (OMIM 310300) and autosomal dominant (EDMD-AD; OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the disease. Mutations in EMD, the gene encoding emerin, are responsible for the X-linked form. We have mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus. This region contains the lamin A/C gene (LMNA), a candidate gene encoding two proteins of the nuclear lamina, lamins A and C, produced by alternative splicing. We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations. These results are the first identification of mutations in a component of the nuclear lamina as a cause of inherited muscle disorder. Together with mutations in EMD (refs 5,6), they underscore the potential importance of the nuclear envelope components in the pathogenesis of neuromuscular disorders.
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              Lamina-Associated Domains: Links with Chromosome Architecture, Heterochromatin, and Gene Repression.

              In metazoan cell nuclei, hundreds of large chromatin domains are in close contact with the nuclear lamina. Such lamina-associated domains (LADs) are thought to help organize chromosomes inside the nucleus and have been associated with gene repression. Here, we discuss the properties of LADs, the molecular mechanisms that determine their association with the nuclear lamina, their dynamic links with other nuclear compartments, and their proposed roles in gene regulation.
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                Author and article information

                Contributors
                Role: Monitoring Editor
                Journal
                Mol Biol Cell
                Mol. Biol. Cell
                molbiolcell
                mbc
                mboc
                Molecular Biology of the Cell
                The American Society for Cell Biology
                1059-1524
                1939-4586
                15 July 2019
                : 30
                : 15
                : 1786-1790
                Affiliations
                [a ]Max F. Perutz Laboratories, Center of Medical Biochemistry, Medical University of Vienna, 1030 Vienna, Austria
                [b ]Department of Biotechnology, University of Natural Resources and Life Sciences, 1190 Vienna, Austria
                University of Virginia
                Author notes
                *Address correspondence to: Roland Foisner ( roland.foisner@ 123456meduniwien.ac.at ) or Selma Osmanagic-Myers ( selma.osmanagic-myers@ 123456boku.ac.at ).
                Article
                E18-10-0672
                10.1091/mbc.E18-10-0672
                6727745
                31306095
                © 2019 Osmanagic-Myers and Foisner. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.

                This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.

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