Lipodystrophic syndromes due to LMNA mutations: recent developments on biomolecular aspects, pathophysiological hypotheses and therapeutic perspectives
Résumé
Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including musculardystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shownto alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within thenucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophicfeatures, combining generalized or partial fat atrophy and metabolic alterations associated withinsulin resistance, could result from altered adipocyte differentiation or from altered fat structure.Recent studies shed some light on how pathogenic A-type lamin variants could triggerlipodystrophy, metabolic complications, and precocious cardiovascular events. Alterations inadipose tissue extracellular matrix and TGF-beta signaling could initiate metabolic inflexibility.Premature senescence of vascular cells could contribute to cardiovascular complications. Inaffected families, metabolic alterations occur at an earlier age across generations, which couldresult from epigenetic deregulation induced by LMNA mutations. Novel cellular modelsrecapitulating adipogenic developmental pathways provide scalable tools for disease modelingand therapeutic screening.
