title: Nesprin-1 mutations in human and murine cardiomyopathy.
abstract: Mutations in LMNA, the gene encoding the nuclear membrane proteins, lamins A and C, produce cardiac and muscle disease. In the heart, these autosomal dominant LMNA mutations lead to cardiomyopathy frequently associated with cardiac conduction system disease. Herein, we describe a patient with the R374H missense variant in nesprin-1alpha, a protein that binds lamin A/C. This individual developed dilated cardiomyopathy requiring cardiac transplantation. Fibroblasts from this individual had increased expression of nesprin-1alpha and lamins A and C, indicating changes in the nuclear membrane complex. We characterized mice lacking the carboxy-terminus of nesprin-1 since this model expresses nesprin-1 without its carboxy-terminal KASH domain. These Delta/DeltaKASH mice have a normally assembled but dysfunctional nuclear membrane complex and provide a model for nesprin-1 mutations. We found that Delta/DeltaKASH mice develop cardiomyopathy with associated cardiac conduction system disease. Older mutant animals were found to have elongated P wave duration, elevated atrial and ventricular effective refractory periods indicating conduction defects in the myocardium, and reduced fractional shortening. Cardiomyocyte nuclei were found to be elongated with reduced heterochromatin in the Delta/DeltaKASH hearts. These findings mirror what has been described from lamin A/C gene mutations and reinforce the importance of an intact nuclear membrane complex for a normally functioning heart.
authors: Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
authors: Megan J
authors: MJ
authors: Puckelwartz
authors: Eric J
authors: EJ
authors: Kessler
authors: Gene
authors: G
authors: Kim
authors: Megan M
authors: MM
authors: Dewitt
authors: Yuan
authors: Y
authors: Zhang
authors: Judy U
authors: JU
authors: Earley
authors: Frederic F S
authors: FF
authors: Depreux
authors: James
authors: J
authors: Holaska
authors: Stephanie K
authors: SK
authors: Mewborn
authors: Peter
authors: P
authors: Pytel
authors: Elizabeth M
authors: EM
authors: McNally
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004452:Echocardiography / Q000379:methods; D005347:Fibroblasts / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000235:genetics; D051379:Mice; D009154:Mutation; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology*
chemical_list: D003598:Cytoskeletal Proteins; D006570:Heterochromatin; D007797:Laminin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C415465:SYNE1 protein, human; C485901:Syne1 protein, mouse; C084098:laminin A