Lipodystrophic syndromes due to LMNA mutations: recent developments on biomolecular aspects, pathophysiological hypotheses and therapeutic perspectives
Abstract
Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular
dystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shown
to alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within the
nucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophic
features, combining generalized or partial fat atrophy and metabolic alterations associated with
insulin 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 trigger
lipodystrophy, metabolic complications, and precocious cardiovascular events. Alterations in
adipose tissue extracellular matrix and TGF-beta signaling could initiate metabolic inflexibility.
Premature senescence of vascular cells could contribute to cardiovascular complications. In
affected families, metabolic alterations occur at an earlier age across generations, which could
result from epigenetic deregulation induced by LMNA mutations. Novel cellular models
recapitulating adipogenic developmental pathways provide scalable tools for disease modeling
and therapeutic screening.