Specific contribution of lamin A and lamin C in the development of laminopathies |
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Authors: | Sylvius Nicolas Hathaway Andrea Boudreau Emilie Gupta Pallavi Labib Sarah Bolongo Pierrette M Rippstein Peter McBride Heidi Bilinska Zofia T Tesson Frédérique |
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Affiliation: | aLaboratory of Genetics of Cardiac Diseases, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Canada K1Y 4W7;bUniversity of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Canada K1Y 4W7;cFirst Department of Cardiac Disease, Institute of Cardiology, Alpejska 42, 04-628 Warsaw, Poland |
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Abstract: | Mutations in the lamin A/C gene are involved in multiple human disorders for which the pathophysiological mechanisms are partially understood. Conflicting results prevail regarding the organization of lamin A and C mutants within the nuclear envelope (NE) and on the interactions of each lamin to its counterpart. We over-expressed various lamin A and C mutants both independently and together in COS7 cells. When expressed alone, lamin A with cardiac/muscular disorder mutations forms abnormal aggregates inside the NE and not inside the nucleoplasm. Conversely, the equivalent lamin C organizes as intranucleoplasmic aggregates that never connect to the NE as opposed to wild type lamin C. Interestingly, the lamin C molecules present within these aggregates exhibit an abnormal increased mobility. When co-expressed, the complex formed by lamin A/C aggregates in the NE. Lamin A and C mutants for lipodystrophy behave similarly to the wild type. These findings reveal that lamins A and C may be differentially affected depending on the mutation. This results in multiple possible physiological consequences which likely contribute in the phenotypic variability of laminopathies. The inability of lamin C mutants to join the nuclear rim in the absence of lamin A is a potential pathophysiological mechanism for laminopathies. |
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Keywords: | Lamin A/C gene Laminopathy Nuclear envelope FRAP Electron microscopy |
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