Communicated by Riccardo Fodde
Article first published online: 27 APR 2007
This article is a U.S. Government work and is in the public domain in the U.S.A. Published in 2007 by Wiley-Liss, Inc.
Volume 28, Issue 9, pages 882–889, September 2007
How to Cite
Moulson, C. L., Fong, L. G., Gardner, J. M., Farber, E. A., Go, G., Passariello, A., Grange, D. K., Young, S. G. and Miner, J. H. (2007), Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes. Hum. Mutat., 28: 882–889. doi: 10.1002/humu.20536
This article is a US government work and, as such, is in the public domain in the United States of America.
- Issue published online: 26 JUL 2007
- Article first published online: 27 APR 2007
- Manuscript Accepted: 6 MAR 2007
- Manuscript Received: 1 AUG 2006
- Progeria Research Foundation
- NIH. Grant Numbers: R01AR049269, AR050200, HL76839, HL086683
- lamin A;
- nuclear lamina;
- restrictive dermopathy;
Hutchinson-Gilford progeria syndrome (HGPS) is a rare precocious aging syndrome caused by mutations in LMNA that lead to synthesis of a mutant form of prelamin A, generally called progerin, that cannot be processed to mature lamin A. Most HGPS patients have a recurrent heterozygous de novo mutation in exon 11 of LMNA, c.1824C>T/p.G608G; this synonymous mutation activates a nearby cryptic splice donor site, resulting in synthesis of the mutant prelamin A, progerin, which lacks 50 amino acids within the carboxyl-terminal domain. Abnormal splicing is incomplete, so the mutant allele produces some normally-spliced transcripts. Nevertheless, the synthesis of progerin is sufficient to cause misshapen nuclei in cultured cells and severe disease phenotypes in affected patients. Here we present two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA. One had a splice site mutation (c.1968+1G>A; or IVS11+1G>A), and the other had a novel synonymous coding region mutation (c.1821G>A/p.V607V). Both mutations caused very frequent use of the same exon 11 splice donor site that is activated in typical HGPS patients. As a consequence, the ratios of progerin mRNA and protein to wild-type were higher than in typical HGPS patients. Fibroblasts from both patients exhibited nuclear shape abnormalities typical of HGPS, and cells treated with a protein farnesyltransferase inhibitor exhibited fewer misshapen nuclei. Thus, farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients. Hum Mutat 28(9), 882–889, 2007. Published 2007 Wiley-Liss, Inc.