Laminopathies of striated muscle are defined as a group of muscular dystrophies associated to dilated cardiomyopathy and conduction and/or rhythm defects (DCM-CD). They are caused by mutations in the LMNA gene encoding two nuclear envelop proteins: lamins A/C (Broers et al. 2006). In 1999 we identified the first laminopathy: autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) (Bonne et al. 1999). Over the last years, LMNA was implicated in more than 10 disorders affecting either single tissue groups (muscular dystrophies/cardiomyopathies (our work), lipodystrophies, axonal neuropathies) or a combination of tissues (premature aging syndromes) (Worman et Bonne, 2007). More recently, we identified mutations in the FHL1 gene in X-linked form of EDMD, identification that extend the clinical spectrum of the mutation of this gene (Gueneau et al, 2009 ; Knoblauch et al, 2010).
Via our collaborative French and European networks on EDMD and other laminopathies and thanks to a technology transfer in 2000 to the Functional Unit of Cardio & Myogenetic (P Richard, Service de Biochimie Métabolique, GH Pitié-Salpêtrière), we have and are still pursuing the characterization of the clinical and genetic spectrum of these disorders. We identified 265 LMNA mutations in 658 individuals displaying a very variable clinical severity, suggesting a continuum between all laminopathies, from isolated cases of dilated cardiomyopathy to fatal foetal akinesia, including muscular dystrophies with variable degrees of severity (Worman et Bonne, 2007; Quijano-Roy et al 2008, Renou et al, 2008). In view of this important diversity, we set up a UMD-LMNA database (www.umd.be/LMNA/) which regroups the clinical and genetic data on all patients carrying a LMNA mutation, reported in the literature and/or by our group. To date, this database contains 344 LMNA mutations found in 1615 individuals and 60% of these presented a striated muscle laminopathy. However, the genetic complexity encompasses more than these various mutations. Germinal mosaics (Makri et al., 2009) or digenism (Muntoni et al. 2006, Ben Yaou et al. 2007) could also contribute to this wide complexity.

 

 

 

Lamins A/C, along with lamin B, delineate the nuclear lamina on the internal side of the nuclear envelop. They interact with numerous proteins of the nuclear envelop, DNA and transcription factors. Their exact role remains elusive: they are thought to participate in replication, transcription, chromatin organization and nuclear envelop structure. The mechanisms by which mutations of the LMNA gene, encoding 2 ubiquitous proteins, cause disorders specifically affecting striated muscle remain to be elucidated.
Several hypotheses have been proposed that attempted to link the pathophysiology of EDMD to known or emerging functions of lamins, emerin or interacting partners. These include ideas surrounding the role of these proteins in maintaining the mechanical integrity of cells (the structural hypothesis), their role in transcription and cell signalling (the gene expression hypothesis), and emerging roles of lamins in adult stem cell differentiation and cellular ageing (the cell proliferation theory) (Worman et Bonne, 2007).

To test these hypotheses, we developed 2 mouse models, LmnaH222P and LmnadelK32, which reproduce 2 mutations that were identified in EDMD patients with a classical or a severe phenotype, respectively. Homozygous LmnaH222P/H222P mice develop a muscular and cardiac dystrophy similar to that seen in EDMD (Arimura et al. 2005). These mice develop neuromuscular junction abnormalities (Mejat et al., 2009) and autophagy may play a protective role via the degradation of cell with abnormally shaped nuclei (Park et al., 2009). Transcriptome analysis showed that their cardiomyopathy correlates with the activation of the MAPK pathway, preceding the onset of clinical signs (Muchir et al. JCI, 2007). Homozygous KI-LmnadelK32 mice die at 15-20 days of age, likely because of metabolic problems and display delayed muscle maturation (Bertrand et al., 2007).

 

 

 

Emphasis is put on the cardiac involvement, because of its severity. In patients with conserved left ventricular function, implanted defibrillator was proven to be useful (Meune et al. 2006). The LmnaH222P mice constitute an excellent model for testing therapeutic approaches. We investigated N-acetylcysteine (NAC), a glutathione precursor, on 6-month old females. A treatment of one month restored glutathione levels, decreased TNF-alpha levels, ameliorated cardiac function and slowed fibrosis progression (Decostre et al. 2007). The inhibition of ERK pathway in asymptomatic mice delay the onset of the cardiomyopathy, and thus seems interesting to be further explore (Muchir et al., 2009).