A.I.5 - Laminopathies: Why make it simple when it can be complex?

Abstract

Laminopathies are a diverse and complex group of rare genetic conditions due to mutations in the LMNA gene encoding Lamin A and C, constituents of the nuclear lamina, a meshwork of proteins underneath the nuclear envelope. Striated muscle laminopathies (SML) are the most frequent type of laminopathies (≈60% of all laminopathies published cases), that affect skeletal and/or cardiac muscle. SMLcomprise LMNA related congenital muscular dystrophy (L-CMD), Emery–Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy, type 1B (LGMD1B) and dilated cardiomyopathy with conduction system disease (DCM-CD). Associated with this wide clinical heterogeneity, there is also a large genetic variability as more than 400 different LMNA mutations have been reported so far (www.umd.be/LMNA/ and unpublished data). In order to get insights in phenotype/genotype relations as well as better knowledge of the natural history of these different clinical entities, we set up a patient registry, OPALE, and initiate an international retrospective natural history study of the early onset SML. Over the years, numerous studies have reported that lamin A/C provide structural support to the nucleus, maintenance of nuclear architecture, nuclear migration, and apoptosis, and also take part in chromatin organization and epigenetics, transcription, cell cycle regulation, cell development and differentiation. To study the role of lamin A/C in skeletal and cardiac muscles, and to understand the pathophysiological processes induced by LMNA mutations, we created knock-in mouse models that reproduced LMNA mutation identified in SML patients. We demonstrated an aberrant increase in MAP kinases in hearts from Lmna H222P knock-in mice, providing proof of principle for MAP kinase inhibition as a therapeutic option to prevent or delay the onset of the contractile dysfunction and cardiomyopathy in SML. Recent insights of the pathophysiological mechanisms of LMNA mutations leading to skeletal and/or cardiac dysfunction in these mouse models will be presented.