title: Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy.
abstract: 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.
authors: Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street. New York, NY 10032, USA.
authors: Antoine
authors: A
authors: Muchir
authors: Paul
authors: P
authors: Pavlidis
authors: Valérie
authors: V
authors: Decostre
authors: Alan J
authors: AJ
authors: Herron
authors: Takuro
authors: T
authors: Arimura
authors: Gisèle
authors: G
authors: Bonne
authors: Howard J
authors: HJ
authors: Worman
mesh_terms: 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*
chemical_list: D034904:Lamin Type A; D020928:Mitogen-Activated Protein Kinases