Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy.
Mutations in LMNA, which encodes nuclear Lamins A and C cause diseases affecting various organs, including the heart. We have determined the effects of an Lmna H222P mutation on signaling pathways involved in the development of cardiomyopathy in a knockin mouse model of autosomal dominant Emery-Dreifuss muscular dystrophy. Analysis of genome-wide expression profiles in hearts using Affymetrix GeneChips showed statistically significant differences in expression of genes in the MAPK pathways at the incipience of the development of clinical disease. Using real-time PCR, we showed that activation of MAPK pathways preceded clinical signs or detectable molecular markers of cardiomyopathy. In heart tissue and isolated cardiomyocytes, there was activation of MAPK cascades and downstream targets, implicated previously in the pathogenesis of cardiomyopathy. Expression of H222P Lamin A in cultured cells activated MAPKs and downstream target genes. Activation of MAPK signaling by mutant A-type lamins could be a cornerstone in the development of heart disease in autosomal dominant Emery-Dreifuss muscular dystrophy.
Muchir
Antoine
A
Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street. New York, NY 10032, USA.
Pavlidis
Paul
P
Decostre
Valérie
V
Herron
Alan J
AJ
Arimura
Takuro
T
Bonne
Gisèle
G
Worman
Howard J
HJ
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D019556:COS Cells; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000235:genetics; D020869:Gene Expression Profiling; D034904:Lamin Type A / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000201:enzymology* / Q000235:genetics*
D034904:Lamin Type A; D020928:Mitogen-Activated Protein Kinases