Résumé :
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Lamins A/C, encoded by the LMNA gene, are intermediate filaments of the nuclear lamina playing multiple roles in nuclear integrity, chromatin organization and transcriptional control. Defects in the LMNA gene have been associated with a growing number of diseases including, among others, skeletal and cardiac muscle defects. In order to describe the biochemical phenotype of neuromuscular laminopathies we undertook proteomic analysis of skin fibroblasts from muscular dystrophy and cardiomyopathy patients carrying LMNA mutations.2D-electrophoresis followed by image analysis and mass spectrometry were employed to identify differentially expressed proteins in lamin A/C patients (18) versus controls, including healthy donors (3) and patients with muscular disorder not related to lamin defects (12). Principal component analysis (PCA) was exploited to identify proteins characterizing different patient groups.We found that LMNA gene mutations not only affect the expression of the mutated gene product itself, but also induce a multitude of other changes mostly in proteins involved in actin cytoskeleton organization, carbohydrate metabolism and oxygen homeostasis. Thus, LMNA mutations can not only disrupt the mechanical coupling between the cytoskeleton and the nucleus leading to a greater susceptibility to physical stress, but as well modify metabolic pathways. To our knowledge, this is the first study where a combination of proteomic procedures was applied to characterise LMNA mutation carriers, suggesting this may represent a new approach to investigate LMNA pathogenetic pathways.
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