Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome

Gordon, Leslie B.; Kleinman, Monica E.; Miller, David T.; Neuberg, Donna; Giobbie‐Hurder, Anita; Gerhard‐Herman, Marie; Smoot, Leslie; Gordon, Catherine M.; Cleveland, Robert H.; Snyder, Brian D.; Fligor, Brian J.; Bishop, W. Robert; Statkevich, Paul; Regen, Amy; Sonis, Andrew L.; Riley, Susan; Ploski, Christine; Correia, Annette; Quinn, Nicolle; Ullrich, Nicole J.; Nazarian, Ara; Liang, Marilyn G.; Huh, Susanna Y.; Schwartzman, Armin; Kieran, Mark W.

doi:10.1073/pnas.1202529109

Cited by 317 publications

(345 citation statements)

References 39 publications

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“…Evidence that the farnesyl modification of these proteins contributes to pathogenesis comes from studies in model mice that lack ZMPSTE24 or that express the HGPS lamin A variant, where treatment with an FTI improves their progeroid phenotypes Yang et al, 2006;Capell et al, 2008). A clinical trial of an FTI has even been carried out in children with HGPS (Gordon et al, 2012). Treatment with statins and aminobisphosphonates has been shown to have similar beneficial effects in mice that lack ZMPSTE24 (Varela et al, 2008).…”

Section: Abnormal Nuclear Morphology and Reversal With An Ftimentioning

confidence: 99%

Mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder

Wang

Lichter‐Konecki

Anyane‐Yeboa

et al. 2016

Journal of Cell Science

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In 1994 in the Journal of Cell Science, Hennekes and Nigg reported that changing valine to arginine at the endoproteolytic cleavage site in chicken prelamin A abolished its conversion to lamin A. The consequences of this mutation in an organism have remained unknown. We now report that the corresponding mutation in a human subject leads to accumulation of prelamin A and causes a progeroid disorder. Next generation sequencing of the subject and her parents' exomes identified a de novo mutation in the lamin A/C gene that resulted in a leucine to arginine amino acid substitution at residue 647 in prelamin A. The subject's fibroblasts accumulated prelamin A, a farnesylated protein, which led to an increased percentage of cultured cells with morphologically abnormal nuclei. Treatment with a protein farnesyltransferase inhibitor improved abnormal nuclear morphology. This case demonstrates that accumulation of prelamin A, independent of loss of function of ZMPSTE24 metallopeptidase that catalyzes it processing, can cause a progeroid disorder and suggests a precision medicine approach to therapy based on results of a cell biological assay.

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Section: Abnormal Nuclear Morphology and Reversal With An Ftimentioning

confidence: 99%

Mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder

Wang

Lichter‐Konecki

Anyane‐Yeboa

et al. 2016

Journal of Cell Science

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“…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).…”

mentioning

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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“…91,96 Frequency of clinical strokes, headaches, and other complications were greatly reduced. 96 Gordon et al recently stated that there is evidence that survival may be improved by FTIs, 97 although they are clearly not curative, many features of the disease persisting despite treatment. The inhibition of isoprenylcysteine methylation, causing accumulation of progerin, could be a further therapeutic approach for HGPS, being able to restore cellular processes in both transgenic mice and human cells.…”

Section: Prospects For Therapeutic Interventionmentioning

confidence: 96%

Emerging perspectives on laminopathies

Lattanzi

Benedetti

D’Apice

et al. 2016

CHC

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Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome

Cited by 317 publications

References 39 publications

Mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder

Mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder

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

Emerging perspectives on laminopathies

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