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.