Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy
| العنوان: | Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy |
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| المؤلفون: | David Chitayat, Judith Melki, Monkol Lek, Stefanie M. Novak, Leigh B. Waddell, Norma B. Romero, Edoardo Malfatti, Jérome Maluenda, Adele D'Amico, Peter J. Houweling, Stacey Gabriel, Livija Medne, Vandana Gupta, Eva Holmberg, Katarina Pelin, James J. Dowling, Carina Wallgren-Pettersson, Ann E. Davidson, Enrico Bertini, Nicole Martin, William R. Telfer, David S. Gokhin, Velia M. Fowler, Yukiko K. Hayashi, Namrata Gupta, Daniel G. MacArthur, Carsten G. Bönnemann, Brett Thomas, Nigel F. Clarke, Ichizo Nishino, Kathryn N. North, Christopher T. Pappas, Carol C. Gregorio, Nigel G. Laing, Lindsay C. Swanson, Catherine A. Brownstein, Darcée D. Sloboda, Pablo Lapunzina, Patrick Shannon, Kate G. R. Quinlan, Natalia Moroz, Coen A.C. Ottenheijm, Alla S. Kostyukova, Peter Van den Bergh, David P. Bick, Ozge Ceyhan-Birsoy, Sarah A. Sandaradura, Annie Laquerrière, Emily J. Todd, Vilma Lotta Lehtokari, Mark J. Daly, Biljana Ilkovski, Alan H. Beggs, Michaela Yuen, Anders Flisberg, Flora Nolent, Gianina Ravenscroft |
| المساهمون: | Department of Medical and Clinical Genetics, Biosciences, Genetics, Faculty of Biological and Environmental Sciences, Haartman Institute (-2014), Physiology, ICaR - Heartfailure and pulmonary arterial hypertension |
| المصدر: | Yuen, M, Sandaradura, S A, Dowling, J J, Kostyukova, A S, Moroz, N, Quinlan, K G, Lehtokari, V L, Ravenscroft, G, Todd, E J, Ceyhan-Birsoy, O, Gokhin, D S, Maluenda, J, Lek, M, Nolent, F, Pappas, C T, Novak, S M, D'Amico, A, Malfatti, E, Thomas, B P, Gabriel, S B, Gupta, N, Daly, M J, Ilkovski, B, Houweling, P J, Davidson, A E, Swanson, L C, Brownstein, C A, Gupta, V A, Medne, L, Shannon, P, Martin, N, Bick, D P, Flisberg, A, Holmberg, E, van den Bergh, P, Lapunzina, P, Waddell, L B, Sioboda, D D, Bertini, E, Chitayat, D, Telfer, W R, Laquerriere, A, Gregorio, C C, Ottenheijm, C A C, Bonnemann, C G, Pelin, K, Beggs, A H, Hayashi, Y K, Romero, N B, Laing, N G, Nishino, I, Wallgren-Pettersson, C, Melki, J, Fowler, V M, MacArthur, D G, North, K N & Clarke, N F 2014, ' Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy ', Journal of Clinical Investigation, vol. 124, no. 11, pp. 4693-4708 . https://doi.org/10.1172/JCI75199Test Journal of Clinical Investigation, 124(11), 4693-4708. The American Society for Clinical Investigation |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Male, Pathology, DNA Mutational Analysis, Gene Expression, Muscle Proteins, TROPOMODULIN, Myopathies, Nemaline, 0302 clinical medicine, Nemaline myopathy, Myofibrils, LENGTH, Cells, Cultured, Zebrafish, 0303 health sciences, biology, Homozygote, Microfilament Proteins, Cardiac muscle, General Medicine, Cell biology, DEFICIENCY, POLYMERIZATION, medicine.anatomical_structure, Gene Knockdown Techniques, SKELETAL-MUSCLE, Female, Corrigendum, Tropomodulin, Research Article, POINTED-END, Heterozygote, medicine.medical_specialty, education, Mutation, Missense, Muscle disorder, ACTIN, 03 medical and health sciences, medicine, Animals, Humans, Genetic Predisposition to Disease, Muscle, Skeletal, Nemaline bodies, Genetic Association Studies, Actin, 030304 developmental biology, MUTATIONS, MUSCLE ALPHA-TROPOMYOSIN, Skeletal muscle, medicine.disease, Congenital myopathy, Actins, 3121 General medicine, internal medicine and other clinical medicine, N-TERMINUS, biology.protein, 3111 Biomedicine, Protein Multimerization, 030217 neurology & neurosurgery |
| الوصف: | Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle. |
| تدمد: | 0021-9738 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::59db3702ea8ec1b098d927c5634cb1caTest https://research.vumc.nl/en/publications/3c042b02-2e92-4398-85b4-5ec89870e352Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....59db3702ea8ec1b098d927c5634cb1ca |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00219738 |
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