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Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy.

Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in the LMNA gene, which encodes lamin A and lamin C. Mutations in this gene also give rise to limb girdle muscular dystrophy type 1B, dilated cardiomyopathy with atrioventricular conduction defect and Dunnigan-type partial lipodystrophy. The properties of the mutant lamins that cause muscular dystrophy, lipodystrophy and dilated cardiomyopathy are not known. We transfected C2C12 myoblasts with cDNA encoding wild-type lamin A and 15 mutant forms found in patients affected by these diseases. Immunofluorescence microscopy showed that four mutants, N195K, E358K, M371K and R386K, could have a dramatically aberrant localization, with decreased nuclear rim staining and formation of intranuclear foci. The distributions of endogenous lamin A/C, lamin B1 and lamin B2 were also altered in cells expressing these four mutants and three of them caused a loss of emerin from the nuclear envelope. In the yeast two-hybrid assay, the 15 lamin A mutants studied interacted with themselves and with wild-type lamin A and lamin B1. Pulse-chase experiments showed no decrease in the stability of several representative lamin A mutants compared with wild-type. These results indicate that some lamin A mutants causing disease can be aberrantly localized, partially disrupt the endogenous lamina and alter emerin localization, whereas others localize normally in transfected cells.

Pubmed ID: 11792809

Authors

  • Ostlund C
  • Bonne G
  • Schwartz K
  • Worman HJ

Journal

Journal of cell science

Publication Data

December 16, 2001

Associated Grants

  • Agency: NCRR NIH HHS, Id: 1S10-RR10506
  • Agency: NCI NIH HHS, Id: 5 P30-CA13696

Mesh Terms

  • Animals
  • COS Cells
  • Cardiomyopathy, Dilated
  • Cell Nucleus
  • Cells, Cultured
  • Fluorescent Antibody Technique
  • Humans
  • Lamin Type A
  • Lamin Type B
  • Lamins
  • Lipodystrophy
  • Mice
  • Muscular Dystrophy, Emery-Dreifuss
  • Mutagenesis, Site-Directed
  • Mutation
  • Nuclear Proteins
  • Protein Precursors
  • Transfection
  • Two-Hybrid System Techniques