Journal Article

An accumulation of non-farnesylated prelamin A causes cardiomyopathy but not progeria

Brandon S.J. Davies, Richard H. Barnes, Yiping Tu, Shuxun Ren, Douglas A. Andres, H. Peter Spielmann, Jan Lammerding, Yibin Wang, Stephen G. Young and Loren G. Fong

in Human Molecular Genetics

Volume 19, issue 13, pages 2682-2694
Published in print July 2010 | ISSN: 0964-6906
Published online April 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq158
An accumulation of non-farnesylated prelamin A causes cardiomyopathy but not progeria

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Lamin A is formed from prelamin A by four post-translational processing steps—farnesylation, release of the last three amino acids of the protein, methylation of the farnesylcysteine and the endoproteolytic release of the C-terminal 15 amino acids (including the farnesylcysteine methyl ester). When the final processing step does not occur, a farnesylated and methylated prelamin A accumulates in cells, causing a severe progeroid disease, restrictive dermopathy (RD). Whether RD is caused by the retention of farnesyl lipid on prelamin A, or by the retention of the last 15 amino acids of the protein, is unknown. To address this issue, we created knock-in mice harboring a mutant Lmna allele (LmnanPLAO) that yields exclusively non-farnesylated prelamin A (and no lamin C). These mice had no evidence of progeria but succumbed to cardiomyopathy. We suspected that the non-farnesylated prelamin A in the tissues of these mice would be strikingly mislocalized to the nucleoplasm, but this was not the case; most was at the nuclear rim (indistinguishable from the lamin A in wild-type mice). The cardiomyopathy could not be ascribed to an absence of lamin C because mice expressing an otherwise identical knock-in allele yielding only wild-type prelamin A appeared normal. We conclude that lamin C synthesis is dispensable in mice and that the failure to convert prelamin A to mature lamin A causes cardiomyopathy (at least in the absence of lamin C). The latter finding is potentially relevant to the long-term use of protein farnesyltransferase inhibitors, which lead to an accumulation of non-farnesylated prelamin A.

Journal Article.  6351 words.  Illustrated.

Subjects: Genetics and Genomics

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