Lamins A/C are ubiquitous nuclear proteins belonging to the intermediate filament family, and "laminopathies" constitute a clinically and genetically heterogeneous group of diseases, affecting a large number of tissues, singly or in combination, including skeletal and cardiac muscles, peripheral nerve, adipose tissue, bone, and skin. These diseases include : Emery-Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (CMD-1A), familial partial lipodystrophy (FPLD), Charcot-Marie-Tooth disease (CMT-2B1), mandibuloacral dysplasia (MAD), LIRLLC, combining generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and hypertrophic cardiomyopathy, Hutchinson-Gilford Progeria syndrome (HGPS), atypical Werner syndrome (WRN), Restrictive Dermopathy (RD) and cases showing different associations of clinical signs. All these diseases are characterized by more or less severe alterations of Lamin A/C expression levels, function and distribution. These alterations can either be primary, due to direct pathogenic sequence variations lying in LMNA, the gene encoding Lamins A/C, or secondary, due to defects in ZMPSTE24, encoding a metalloproteinase involved in prelamin A post-translational processing.
Indeed, while Lamin A and C mRNAs are produced through pre-mRNA alternative splicing, mature Lamin A is further obtained through a multi-step post-translational processing of a protein precursor “prelamin A”. LMNA mutations responsible for the majority of laminopathies are distributed all along the gene, involving both Lamins A and C, while mutations causing the more severe accelerated aging syndromes HGPS and RD, lie in Lamin A-specific exon 11. Recent evidence has shown that the latter syndromes are caused by intranuclear accumulation of unprocessed prelamin A, due to intrinsic lack of key post-translational processing sites or to lack of ZMPSTE24 processing enzyme. Furthermore, it has been showed in vitro and in vivo, in mouse models, that reduction of the amounts of precursors produced by the cells can spectacularly reverse the cellular pathological phenotype. These observations constitute indeed an exciting hope towards targeted molecular therapeutic strategies in patients.