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

Abstract

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.

• Authors: C Ostlund, G Bonne, K Schwartz, H J Worman
• Journal: Journal of cell science (J Cell Sci) Vol. 114 Issue Pt 24 Pg. 4435-45 (Dec 2001) ISSN: 0021-9533 [Print] England
• PMID: 11792809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Lamin Type A
• Lamin Type B
• Lamins
• Nuclear Proteins
• Protein Precursors
• lamin B1
• lamin B2
• lamin C
• prelamin A

Topics

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