title: An accumulation of non-farnesylated prelamin A causes cardiomyopathy but not progeria.
abstract: 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.
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Brandon S J
authors.initials: BS
authors.lastname: Davies
authors.forename: Richard H
authors.initials: RH
authors.lastname: Barnes
authors.forename: Yiping
authors.initials: Y
authors.lastname: Tu
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Andres
authors.forename: H Peter
authors.initials: HP
authors.lastname: Spielmann
authors.forename: Jan
authors.initials: J
authors.lastname: Lammerding
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques; D034904:Lamin Type A / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011371:Progeria / Q000209:etiology / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism*; D017368:Protein Prenylation
chemical_list: D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C440308:lamin C; C090764:prelamin A