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 Pathologies linked to lamins: a new and very
promising field of investigation on the border between the muscle and premature
aging mechanisms
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  At last – a good animal model for
FSH!
Facioscapulohumeral (FSH) dystrophy is a muscle disease mainly associated with contractions of the telomeric region D4Z4 located on 4q35. Several teams have shown that three genes situated upstream of the D4Z4 and physiologically silent, were in fact over-expressed in FSH. The over-expression of these three genes, ANT1, FRG1 and FRG2 could be at the origin of this myopathy, which has remained without explanation for a number of years. Rossela Tupler (researcher at the University of Massachussets of Worcester, and scientific leader of the French Club for FSH) has succeeded in creating a mouse model for each of these three genes in the hope of developing a suitable model for FSH. Although the mice over-expressing FRG2 and ANT1 did not present any particular phenotype, especially muscular, this was not true for FRG1. The animals where the FRG1 gene was specifically over-expressed at muscle level developed progressive muscular dystrophy which selectively affected certain muscles, as in man. These FRG 1+/+ mice present also muscle atrophy and are intolerant of exercise. Moreover, the severity of the disease is clearly correlated with the level of over-expression of the FRG1 protein. The creation of the FRG1+/+ mouse thus represents a great advance in the understanding of this myopathy whose genetic mechanisms still remain obscure. In time, this line of mice could be very useful to test different therapeutic hypotheses. > Contribution by Rossella Tupler, wednesday 11 may 9h30 |
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