Muscular laminopathies: Role of prelamin A in early steps of muscle differentiation
Nadir M. MaraldiCristina CapanniRosalba Del CocoStefano SquarzoniMarta ColumbaroElisabetta MattioliGiovanna LattanziFrancesco A. Manzoli
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The muscular dystrophies (MDs) result from perturbations in the myofibers. These alterations are induced in part by mechanical stress due to membrane cell fragility, disturbances in mechanotransduction pathways, muscle cell physiology, and metabolism.We analyzed 290 biopsies of patients with a clinical diagnosis of muscular dystrophy. Using immunofluorescence staining, we searched for primary and secondary deficiencies of 12 different proteins, including membrane, costamere, cytoskeletal, and nuclear proteins. In addition, we analyzed calpain-3 by immunoblot.We identified 212 patients with varying degrees of protein deficiencies, including dystrophin, sarcoglycans, dysferlin, caveolin-3, calpain-3, emerin, and merosin. Moreover, 78 biopsies showed normal expression of all investigated muscle proteins. The frequency rates of protein deficiencies were as follows: 52.36% dystrophinopathies; 18.40% dysferlinopathies; 14.15% sarcoglycanopathies; 11.32% calpainopathies; 1.89% merosinopathies; 1.42% caveolinopathies; and 0.47% emerinopathies. Deficiencies in lamin A/C and telethonin were not detected.We have described the frequency of common muscular dystrophies in Mexico.
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Limb-girdle muscular dystrophy
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Emerin and lamins are nuclear proteins, which are missing or defective in Emery-Dreifuss muscular dystrophy (EDMD). The aim of this study was to test the expression of these proteins in skeletal muscles in the X-linked (X-EDMD) and autosomal dominant (AD-EDMD) form. The study group consisted of 11 patients with X-EDMD, 11 patients of the AD-EDMD and 20 age-matched normal subjects. Expression of emerin and lamins in muscles were analyzed by Western blotting and the immunocytochemical technique. Using the Western blotting procedure emerin was detected in traces in the X-linked form. In the majority of these cases (6/11) it was connected with a decreased concentration of lamin A, in four patients a lowered concentration of lamin C was present. Lamin B2 was either normal (8/11), or decreased (3/11). Deficit of lamin A was a characteristic feature for AD-EDMD in the majority of these cases (9/11), while in two of these patients a decrease of lamin C, in four cases a lowered level of emerin was also present. In one AD-EDMD patient of a decrease of lamin C, but normal lamin A was present. Following the immunocytochemical examination the decrease of lamin A/C in X-EDMD and of emerin in AD-EDMD was also observed. The above mentioned data demonstrated that in X-EDMD and AD-EDMD the deficit of the appropriate proteins is not restricted either to emerin or lamins. The defect is more widespread and results in disruption of several nuclear proteins. This study also indicated that for the diagnostic EDMD purposes the immunocytochemical detection of emerin/lamins has to be accomplished by quantitative immunochemical analyses of the above mentioned proteins.
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The human genome is contained within the nucleus and is separated from the cytoplasm by the nuclear envelope. Mutations in the nuclear envelope proteins emerin and lamin A cause a number of diseases including premature aging syndromes, muscular dystrophy, and cardiomyopathy. Emerin and lamin A are implicated in regulating muscle- and heart-specific gene expression and nuclear architecture. For example, lamin A regulates the expression and localization of gap junction and intercalated disc components. Additionally, emerin and lamin A are also required to maintain nuclear envelope integrity. Demonstrating the importance of maintaining nuclear integrity in heart disease, atrioventricular node cells lacking lamin A exhibit increased nuclear deformation and apoptosis. This review highlights the present understanding of lamin A and emerin function in regulating nuclear architecture, gene expression, and cell signaling and discusses putative mechanisms for how specific mutations in lamin A and emerin cause cardiac- or muscle-specific disease.
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Emerin (34 kDa) is a 254 amino acid protein located on the cytoplasmic surface of the inner nuclear membrane in cardiac muscle. It interacts with nuclear lamins and nuclear actin. Emerin is usually completely absent in Emery-Dreifuss muscular dystrophy, a condition that also manifests in the heart. Nuclear lamins are specialized nuclear proteins that line the inner nuclear membrane. Two isoforms, lamin A and C, differ in their C-terminal amino acids. Both are important in apoptosis and are degraded by caspase enzymes. Mutations in the rod domain of the lamin A/C gene are known to cause dilated cardiomyopathy (DCM) (Fatkin et al. New Engl. J. Med. 1999, 351, 1715–1724). We have used Western blots to detect emerin and lamin A/C in left ventricles from both nondiseased and failing DCM samples. The lamins form dimers, however it is not known if they are homodimers and / or heterodimers. In this report we compare and quantify expression levels of emerin from samples of left ventricles from ten failing DCM patients and five nondiseased (donor) hearts. We observed three lamin bands that suggest the expression of the three isoforms of the A-type lamin gene, lamin A, lamin C and lamin C2 (Ye et al. Subcellular Biochem. 1998, 31, 587–610). Preliminary data show that both lamin isoforms and emerin are present.
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Journal Article Interaction between Emerin and Nuclear Lamins Get access Masayo Sakaki, Masayo Sakaki *Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo3-8-1 Komaba, Meguro-ku, Tokyo 153-8902 Search for other works by this author on: Oxford Academic PubMed Google Scholar Hisashi Koike, Hisashi Koike †Department of Biochemistry, Meiji Pharmaceutical University2-522-1 Noshio, Kiyose, Tbkyo 204-8588 Search for other works by this author on: Oxford Academic PubMed Google Scholar Nobuhiro Takahashi, Nobuhiro Takahashi *Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo3-8-1 Komaba, Meguro-ku, Tokyo 153-8902 Search for other works by this author on: Oxford Academic PubMed Google Scholar Noboru Sasagawa, Noboru Sasagawa *Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo3-8-1 Komaba, Meguro-ku, Tokyo 153-8902 Search for other works by this author on: Oxford Academic PubMed Google Scholar Shigeo Tomioka, Shigeo Tomioka ‡Department of Molecular Biology, Institute of Molecular and Cellular Bioscience, University of Tokyo1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032 Search for other works by this author on: Oxford Academic PubMed Google Scholar Kiichi Arahata, Kiichi Arahata §Department of Neuromuscular Research, National Institute of NeuroscienceNCNP, Tokyo 187-8502 Search for other works by this author on: Oxford Academic PubMed Google Scholar Shoichi Ishiura Shoichi Ishiura 2 *Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo3-8-1 Komaba, Meguro-ku, Tokyo 153-8902 2To whom correspondence should be addressed. Phone: +81-3-5454-6739, Fax: +81-3-5454-6739, cishiura@mail.eccu-tokyo.ac.jp Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Biochemistry, Volume 129, Issue 2, February 2001, Pages 321–327, https://doi.org/10.1093/oxfordjournals.jbchem.a002860 Published: 01 February 2001 Article history Received: 05 September 2000 Accepted: 05 December 2000 Published: 01 February 2001
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