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Fong; An accumulation of non-farnesylated prelamin A causes cardiomyopathy but not progeria, Human Molecular GeneticsVolume 19, Issue 13, 1 JulyPages —, https: 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 Lmna nPLAO 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.

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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. Lamin A, a key component of the nuclear lamina, is formed from a precursor protein, prelamin A, by four enzymatic post-translational processing steps—farnesylation of a cysteine located four amino acids from the C terminus of the protein, endoproteolytic cleavage of the last three amino acids of the protein, carboxyl methylation of the newly exposed farnesylcysteine and endoproteolytic release of the last 15 amino acids of the protein including the farnesylcysteine methyl ester 1—5.

The last endoproteolytic cleavage step, which releases mature lamin A, is carried out by ZMPSTE24, a membrane zinc metalloproteinase of the endoplasmic reticulum 6—9. Defects in prelamin A processing and lamin A biogenesis have been linked to progeroid disorders in humans. This deletion does not affect the C-terminal farnesylation or methylation, but it does remove the site for the last ZMPSTE24 cleavage event.

The elimination of the final processing step causes an accumulation of a truncated prelamin A, commonly called progerin, that retains a C-terminal farnesylcysteine methyl ester 11 Aside from the farnesylcysteine methyl ester, progerin contains four additional C-terminal residues that are not found in mature lamin A.

Progerin adversely affects the integrity and function of the nuclear lamina, leading to misshapen nuclei in cultured cells and a host of aging-like disease phenotypes 10 Recently, Yang et al. However, recent genetic studies in mice have suggested that the FTI treatment strategy may be destined to fall short of a complete cure.

The finding that non-farnesylated progerin elicits disease suggested that an altered primary structure i. ZMPSTE24 deficiency abolishes the final processing step that releases mature lamin A, resulting in an accumulation of a farnesylated and methylated prelamin A.

It does, however, retain the extra 15 amino acids at its C terminus—the segment that is normally absent in mature lamin A.

One possibility is that disease is largely due to the retention of the farnesyl lipid at the C terminus of prelamin A. However, there are other possibilities. For example, one could reasonably speculate that the extra 15 amino acids at prelamin A’s C terminus—and not the lipid anchor—elicit disease. In the current study, we tested the hypothesis that the retention of the last 15 amino acids of prelamin Sipelmanns is sufficient to elicit progeria in mice.


To approach this issue, we created and analyzed Lmna knock-in mice that produce exclusively non-farnesylated baufh A. We created Lmna knock-in mice expressing exclusively non-farnesylated prelamin A or exclusively wild-type prelamin A. Targeted embryonic stem ES cell clones Fig.

Heterozygotes were then intercrossed to produce homozygotes. Production of knock-in mice that express a non-farnesylated version of prelamin A or wild-type prelamin A. This vector removes introns 10 and 11 thereby abolishing synthesis of lamin C and introduces a point mutation that changes the cysteine in the CaaX motif to a serine bauxh abolishing protein prenylation.

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This vector removes introns 10 and 11 but leaves the CaaX motif intact. C Southern blot identification of targeting events in ES cell clones. Actin levels were xes as a loading control.

Treatment of fibroblasts with an FTI prevents farnesylation of prelamin A and thus prevents the multistep pathway that converts prelamin A to mature lamin A 12 Actin was used as a loading control. B Metabolic labeling experiment with a farnesol analog, AG to assess the farnesylation of prelamin A. A non-specific band was also observed in the AG western blot electrophoretic band immediately beneath lamin C.

In wild-type mouse fibroblasts, lamin A was present at the nuclear rim, but significant amounts were also found in the nucleoplasm Fig. Nuclei were counterstained with DAPI blue. Images were taken with a confocal microscope.

We examined fibroblasts that had been immortalized by repeated passaging D and spielmznns low-passage number primary embryonic fibroblasts E. The extent of nuclear deformations was measured and is expressed as a ratio of nuclear strain to applied membrane strain normalized nuclear strain.

This cardiomyopathy phenotype, with a greater severity in males, is similar to the phenotype of Lmna knock-in mice carrying an HP substitution Fibrotic tissue is stained green. In humans, lamin-related progeroid syndromes are associated with osteolytic lesions in bones, a severe growth defect, and reduced survival 1027 Arrowheads indicate rib fractures and surrounding callus.

Scale bars represent 2. Indeed, this was the case. When ZMPSTE24 is absent, are the disease phenotypes elicited by the retention of the hydrophobic lipid anchor on prelamin A or are they due to the extra 15 amino acids at the protein’s C terminus? To our surprise, this hypothesis was proven wrong. Clearly, non-farnesylated prelamin A is not functionally equivalent to mature lamin A.

The involvement of Lmna in cardiomyopathy is not without precedent. Several of the missense mutations observed in humans have been introduced into mouse Lmnaand homozygous mice for those mutations manifest cardiomyopathy and premature death 26 Interestingly, no one has yet found a case of cardiomyopathy due to a missense mutation involving the last 15 amino acids of prelamin A, nor has anyone identified a CaaX motif mutation leading to the production of non-farnesylated prelamin A.

The conclusion that non-farnesylated prelamin A leads to cardiomyopathy, but not progeria, is subject to several caveats. Thus, one could conceivably postulate that the cardiomyopathy is elicited by the inability to make that lamin isoform.

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It remains a formal possibility that cardiomyopathy is caused by non-farnesylated prelamin A, but only in the absence of lamin C.

That amino acid substitution is remarkably subtle, amounting dea replacing a single sulfur atom with an oxygen atom. Nevertheless, one could propose that this amino acid substitution is solely responsible for the cardiomyopathy. Unfortunately, we are not aware of any strategy that would make this possible.

In theory, one could achieve this goal by eliminating the expression of FTase, a genetic intervention that would lead to the accumulation of non-farnesylated prelamin A For such an approach to be practical, however, FTase deficiency could not elicit any of its own untoward consequences. Unfortunately, bxuch is not the case. A complete deficiency of FTase causes early embryonic lethality Although initially reported that a knockout of FTase in adult mice leads buch little if any pathology 37it is now clear that this is not the case.


FTase deficiency in skin keratinocytes yields severe alopecia 34and an absence of FTase in liver causes severe hepatocellular disease Shao H. In earlier studies, Fong et al.

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In the future, it is conceivable that newer and more sensitive assays could uncover unique and important physiologic roles for each of the two protein isoforms. Dogma has spielmwnns that prelamin A’s hydrophobic lipid anchor is important for the targeting of the protein to the inner nuclear membrane which is adjacent to the nuclear lamina.

wpielmanns In part, this conclusion rested on the observation that prelamin A appears in the nucleoplasm of cultured fibroblasts, rather than at the nuclear rim, det protein farnesylation is inhibited A third study found that some non-farnesylated prelamin A reached the nuclear rim, but with delayed kinetics Recently, however, the conclusion that farnesylation is important for the nuclear envelope targeting of prelamin A has been challenged.

Lamin C, which bakch never farnesylated, reaches the nuclear rim, even in the absence of lamin A, suggesting that farnesylation is not a requirement for nuclear rim localization of that nuclear lamin Taking advantage of a new monoclonal antibody against mouse prelamin A, Lee et al.

Little if any non-farnesylated prelamin A was found in the nucleoplasm. In the current study, we observed consistent findings. Thus, prelamin A’s farnesyl lipid anchor is not required for targeting to the nuclear rim.

Several years ago, Fong et al. Those findings supported the concept that farnesyl-prelamin A is toxic and provided the first suggestion that strategies to reduce prelamin A production could be therapeutically useful in progeria. Larger amounts of farnesyl-prelamin A clearly lead to more toxicity: From the standpoint of therapy, the gauch study would suggest that an FTI has the potential to be a double-edged sword. On the one hand, our findings suggest that reducing protein farnesylation with an FTI might be useful, in that non-farnesylated prelamin A appears to be devoid of the capacity to elicit progeria-like disease phenotypes.

On bquch other hand, our studies offer a darker possibility—that non-farnesylated prelamin A carries its own distinctive toxicity, dilated cardiomyopathy. Thus, it is theoretically possible that any accumulation of non-farnesylated prelamin A, such as would occur with a long-term FTI therapy, could adversely affect the heart. Fortunately, we are not aware of any reports of cardiomyopathy with FTI therapy in humans, nor have we observed any spielmqnns of cardiomyopathy when treating mice with an FTI, but any physician contemplating long-term FTI treatment for progeroid spielmanjs should be attuned to this epielmanns.

To create a mutant Lmna allele yielding only non-farnesylated prelamin A Lmna nPLAOwe used a gene-targeting vector similar to one used to create a mutant allele yielding exclusively progerin Lmna HG Also, a point mutation was introduced into exon 12 that changes the cysteine of prelamin A’s CaaX motif to a serine i. The integrity of both gene-targeting vectors was verified by restriction endonuclease digestion and DNA sequencing.

All mice were fed a chow diet and housed in a virus-free barrier facility with a 12 h light—dark cycle. Primary mouse embryonic fibroblasts were prepared from fes day Urea-soluble extracts were prepared as described previously Antibody dilutions were 1: The IR-coupled antibodies were detected with an Odyssey infrared imaging scanner and dder according to the manufacturer’s instructions.

The incorporation of AG into CaaX proteins such as prelamin A can be detected by western blotting with an AG-specific mouse monoclonal antibody 1: Deg assess nuclear shape abnormalities, early-passage mouse embryonic fibroblasts were grown on coverslips and then fixed and permeabilized 8.

Cells were incubated with antibodies against lamin A 1: After washing, cells were incubated with Alexa Fluor conjugated anti-rabbit antibody 1: