LMNA gene encodes the nuclear A-type lamins. LMNA mutations are associated with more than 10 clinical entities and represent one of the first causes of inherited dilated cardiomyopathy. LMNA-dilated cardiomyopathy is associated with conduction disease (DCM-CD) and is a severe and aggressive form of DCM. However, pathogenesis remains largely unknown and no specific treatment is currently available for the patients. In this review, we present recent discoveries that improve the understanding of the cardiac pathophysiological roles of A-type lamins and shed light on potential therapeutic targets.
In the last decade, many efforts have been made to elucidate how mutations in A-type lamins, ubiquitous proteins, lead to DCM-CD. No clear genotype/phenotype correlations have been found to help in elucidating those mechanisms. Analysis of several mouse models has helped in deciphering critical pathomechanisms. Among those, Mitogen-activated protein kinases (MAPK) and Akt/mTOR appear to be key early-activated signaling pathways in LMNA DCM-CD in both humans and mice. Inhibition of these signaling pathways has shown encouraging beneficial effects upon cardiac evolution of DCM-CD.
These recent findings suggest that targeting MAPK and Akt/mTOR pathways with potent and specific compounds represents a promising intervention for the treatment of LMNA DCM-CD.
bUniversité Pierre et Marie Curie – Paris 6, UM 76, CNRS, UMR 7215, Institut de Myologie
cAP-HP, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, France
Correspondance to Gisèle Bonne, Thérapie des maladies du muscle strié/Institut de Myologie, Inserm, U974, G.H. Pitié-Salpêtrière, 47 boulevard de l’Hôpital, F-75 651 Paris Cedex 13, France. Tel: +331 421 657 23; fax: +331 421 657 00; e-mail: email@example.com