Résumé :
|
Lamins, a class of intermediate filaments, are major components of the nuclear lamina, a filamentous network underlying the inner face of the nuclear membrane. A-type Lamins are encoded by the same gene: LMNA, regulated by the AP1 complex (c-Fos & c-Jun). Up to date, eleven pathologies, described as laminopathies, have been associated with mutations in LMNA. One of these, Charcot-Marie-Tooth disease (CMT), type 2B1, is an autosomal recessive form of axonal CMT caused by the c.892C>T transition in LMNA exon 5. (p.Arg298Cys). In order to progress towards understanding of the pathophysiological mechanisms underlying CMT2B1, we studied two different models for the disease: human cells from patients homozygous for the c.892C>T mutation, and a Knock-In LmnaR298C/R298C mouse model. Gene expression studies performed on human microfluidic plates (Low Density Arrays) evidenced significant decrease in expression levels of several genes, including LMNA. These observations were confirmed in mouse brain, skeletal and cardiac muscle, sciatic nerve and spinal cord at the transcriptional level, as well as on lymphoblastoid human cell lines at the protein level. The p.Arg298Cys mutation lies within a coil-coiled domain, an important functional domain for intermediate filament polymerization. In silico predictions are in favor of a potential destabilizing effect of the mutation. Moreover, previous publications have shown that Lamins interact with c-Fos, a Leucine Zipper transcription factor, through their coiled-coil domain.We therefore propose a two-hit pathophysiological mechanism model: - The pArg298Cys mutation might destabilize complexes between A-type Lamins and transcription factors: the latter might be either components of the AP1 complex, or some nerve specific transcription factors, which remain to be identified. - LMNA seems to be autoregulated through an A_type Lamins – AP1 complex, which might be disrupted at the DNA level by the presence of the mutation. We are actually conducting further experiments in order to confirm these hypotheses.
|