Laminopathies are a group of clinically and genetically heterogeneous diseases due to lamins A/C defects. This group includes Emery-Dreifuss autosomal dominant muscular dystrophy (EDAD-MD), one of the limb-girdle myopathies, a form of Charcot-Marie-Tooth disease and certain premature aging syndromes. Over the last two years, research has accelerated in this field with the discovery of nine new pathologies and a progressive understanding of the physiopathological mechanism which underlies them.
Lamins A/C are proteins located under the membrane which surrounds the nucleus of the cell containing the chromosomes. They are encoded by a single LMNA gene. The process of maturation of lamin A depends on an enzyme called ZMPSTE24 or FACE-1. Recent studies have shown that certain extremely serious premature aging syndromes were due either to LMNA or to FACE-1 mutations. Nicolas Lévy (professor of genetics at the Timone Hospital in Marseille and laminopathies specialist) has indicated a major advance in the understanding of the physiopathological mechanism of two very rare premature aging syndromes (Hutchinson-Gilford progeria and restrictive dermopathy), which are probably linked to a toxic accumulation of lamin A precursor (pre-lamin A) in the nucleus. Indeed, in the absence of FACE-1 or due to precise mutations of LMNA, pre-lamin A does not go through its normal maturation phase and accumulates in the nucleus. Moreover, in vitro and in vivo studies on mice models of these pathologies have shown that the reduction in level of pre-lamin A can not only correct the anomalies of affected cell nuclei, but also clinical anomalies – and these in a stable satisfactory manner.
These observations constitute a very important step towards the application of therapeutic strategies in patients affected by these particularly disabling genetic diseases.
> Plenary lecture by Nicolas Lévy, wednesday 11 may 8h30