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

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

doi:10.1093/hmg/ddq158

Cited by 104 publications

(138 citation statements)

References 48 publications

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“…[38][39][40][41] However, recent studies with a CAAX motif mutant or mice lacking farnesyltransferase expression in keratinocytes suggested that, at least for LA, incorporation into the lamina does not require farnesylation. 42,43 The only two studies …”

Section: Resultsmentioning

confidence: 99%

Disruption of lamin B1 and lamin B2 processing and localization by farnesyltransferase inhibitors

Adam¹,

Butin‐Israeli²,

Cleland³

et al. 2013

Nucleus

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Section: Resultsmentioning

confidence: 99%

Disruption of lamin B1 and lamin B2 processing and localization by farnesyltransferase inhibitors

Adam¹,

Butin‐Israeli²,

Cleland³

et al. 2013

Nucleus

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“…The "mature lamin A" mice were healthy and fertile, and the lamin A in their tissues was positioned normally along the rim of the cell nucleus, indistinguishable from lamin A in the tissues of wild-type mice. Davies et al (37) found that mice expressing nonfarnesylated prelamin A developed cardiomyopathy late in life, but the nonfarnesylated prelamin A was positioned normally at the nuclear rim. Neither the distinctive phenotypes of mature lamin A and nonfarnesylated prelamin A mice nor the nuclear rim localization of the lamin A proteins in these mice could have been predicted from cell culture studies alone.…”

Section: Discussionmentioning

confidence: 99%

Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Jung¹,

Nobumori²,

Goulbourne³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left "naked" (free from the nuclear lamina). Thus, farnesylation of lamin B1-but not lamin B2-is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.genetically modified mouse models T he nuclear lamina is an intermediate filament meshwork that lies beneath the inner nuclear membrane. This lamina provides structural support for the nucleus and also interacts with nuclear proteins and chromatin, thereby affecting many functions within the cell nucleus (1, 2). In mammals, the main protein components of the nuclear lamina are lamins A and C (A-type lamins) and lamins B1 and B2 (B-type lamins).Both B-type lamins and prelamin A (the precursor of lamin A) terminate with a CaaX motif, which triggers three posttranslational modifications (3-5): farnesylation of the carboxyl-terminal cysteine (the "C" in the CaaX motif) (6), endoproteolytic cleavage of the last three amino acids (the -aaX) (7,8), and carboxyl methylation of the newly exposed farnesylcysteine (9, 10). Prelamin A undergoes a second endoproteolytic cleavage event, mediated by zinc metalloproteinase STE24 (ZMPSTE24), which removes 15 additional amino acids from the carboxyl terminus, including the farnesylcysteine methyl ester (11)(12)(13)(14). Lamins B1 and B2 do not undergo the second cleavage step and therefore retain their farnesyl lipid anchor.The discovery that Hutchinson-Gilford progeria syndrome (HGPS) is caused by a LMNA mutation yielding an internally truncated farnesyl-prelamin A (15) has focused interest in the farnesylation of nuclear lamins. This interest has been fueled by the finding that disease phenotypes in mouse models of HGPS could be ameliorated by blocking protein farnesylation with a protein farnesyltransferase inhibitor (FTI) (16)(17)(18)(19). Most recently, children with HGPS seemed to show a positive response to FTI treatment (20).The prospect of using an FTI to treat children with HGPS naturally raises the issue of the importance of protein farnesylation for lamin B1 and lamin B2. The B-type lamins are expressed in all mammalian cells and have been h...

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“…Lmna nPLAO/nPLAO mice, expressing only non-farnesylated prelamin A, appeared normal for the first 20 weeks of life, but developed a cardiomyopathy and died earlier than healthy mice (median survival in female mice 49.5 weeks, in male mice 38.5 weeks). 23 By contrast, the presence of farnesylated progerin next to mature lamin A in classical HGPS disturbs the nuclear integrity and results in the typical progeroid phenotype with death in early adolescence.…”

Section: Discussionmentioning

confidence: 99%

Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn

et al. 2012

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Hutchinson-Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C4T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G4A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria.

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

Cited by 104 publications

References 48 publications

Disruption of lamin B1 and lamin B2 processing and localization by farnesyltransferase inhibitors

Disruption of lamin B1 and lamin B2 processing and localization by farnesyltransferase inhibitors

Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn

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