Yang, S. H. et al. Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation. Proc. Natl Acad. Sci. USA 102, 10291-10296

Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2005; 102(29):10291-6. DOI: 10.1073/pnas.0504641102
Source: PubMed


Hutchinson-Gilford progeria syndrome (HGPS), a progeroid syndrome in children, is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a "CAAX protein" that is farnesylated and then processed further to generate mature lamin A, which is a structural protein of the nuclear lamina. The mutant prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesylation, but the 50-aa deletion prevents the subsequent processing to mature lamin A. The presence of progerin adversely affects the integrity of the nuclear lamina, resulting in misshapen nuclei and nuclear blebs. We hypothesized that interfering with protein farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothesized that the mislocalization of progerin away from the nuclear envelope would improve the nuclear blebbing phenotype. To approach this hypothesis, we created a gene-targeted mouse model of HGPS, generated genetically identical primary mouse embryonic fibroblasts, and we then examined the effect of a farnesyltransferase inhibitor on nuclear blebbing. The farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleoplasm, as determined by immunofluoresence microscopy, and resulted in a striking improvement in nuclear blebbing (P < 0.0001 by chi2 statistic). These studies suggest a possible treatment strategy for HGPS.

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    • "Most of the HGPS cases (around 90%) carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA which activates a splice donor site that results in production of a dominant negative form of the lamin A protein22. LMNA gene is present on chromosome 1 and the point mutation results in the deletion of 50 amino acids of prelamin A23 which destabilizes the nucleus further and is fatal for the cell. Cells with abnormal nuclear shape are often implicated in a number of disease pathologies in which lamin A proteins are mutated, collectively referred to as laminopathies24. "
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    ABSTRACT: Progeria is characterized by clinical features that mimic premature ageing. Although the mutation responsible for this syndrome has been deciphered, the mechanism of its action remains elusive. Progeria research has gained momentum particularly in the last two decades because of the possibility of revealing evidences about the ageing process in normal and other pathophysiological conditions. Various experimental models, both in vivo and in vitro, have been developed in an effort to understand the cellular and molecular basis of a number of clinically heterogeneous rare genetic disorders that come under the umbrella of progeroid syndromes (PSs). As per the latest clinical trial reports, Lonafarnib, a farnesyltranferase inhibitor, is a potent 'drug of hope' for Hutchinson-Gilford progeria syndrome (HGPS) and has been successful in facilitating weight gain and improving cardiovascular and skeletal pathologies in progeroid children. This can be considered as the dawn of a new era in progeria research and thus, an apt time to review the research developments in this area highlighting the molecular aspects, experimental models, promising drugs in trial and their implications to gain a better understanding of PSs.
    The Indian Journal of Medical Research 05/2014; 139(5):667-74. · 1.40 Impact Factor
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    • "Insertion of the truncated progerin into the nuclear lamina causes defective cell mitotic behaviour and chromosome segregation, genomic instability and widespread transcriptional changes, resulting in cellular senescence and premature ageing [30] [31] [32]. It is believed that the farnesyl group plays a major role in the negative dominant effect of progerin [33] [34] [35]. "
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    ABSTRACT: Some features of sporadic inclusion body myositis (s-IBM) suggest that there is acceleration of the normal ageing process in muscle tissue. LMNA encodes the nuclear lamina proteins lamin A/C through alternative splicing, and aberrant splicing of exon 11 leads to the premature ageing disease, Hutchinson-Gilford progeria syndrome. Progerin, the pathogenic isoform expressed in HGPS tissues, has also been detected at low levels in tissues of normal individuals with aging. We therefore investigated the alternative splicing of LMNA gene transcripts, and the post-translational processing of prelamin A, in s-IBM and control muscle samples. Age-related low level expression of the progerin transcript was detected in both s-IBM and control muscles, but was not increased in s-IBM and there was no increase in progerin protein or demonstrable accumulation of intermediate prelamin isoforms in the s-IBM muscles. However, an age-related shift in the balance of splicing towards lamin A-related transcripts, which was present in normal muscles, was not found in s-IBM. Our findings indicate that while there are changes in the patterns of LMNA splicing in s-IBM muscle which are probably secondary to the underlying pathological process, it is unlikely that aberrant splicing of exon 11 or defective post-translational processing of prelamin A are involved in the pathogenesis of the disease.
    International journal of clinical and experimental pathology 09/2013; 6(9):1723-33. · 1.89 Impact Factor
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    • ") demonstrated that blocking farnesylation of progerin or prelamin A with farnesyltransferase inhibitors (FTIs) could alleviate progeriod phenotypes (Capell et al., 2005; Yang et al., 2005; Fong et al., 2006a; Yang et al., 2006; Capell et al., 2008). In addition, Davies et al. created a knock-in mouse model that carries a nonfarnesylated prelamin A and reported that these animals developed a dilated cardiomyopathy but had no phenotypes of progeria (Davies et al., 2010). "
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    ABSTRACT: The A- and B-type lamins are nuclear intermediate filament proteins in eukaryotic cells with a broad range of functions, including the organization of nuclear architecture and interaction with proteins in many cellular functions. Over 180 disease-causing mutations, termed "laminopathies", have been mapped throughout LMNA, the gene for A-type lamins in humans. Laminopathies can range from muscular dystrophies, cardiomyopathy, to Hutchinson Gilford progeria syndrome. A number of mouse lines carrying some of the same mutations as those resulting in human diseases have been established. These LMNA-related mouse models have provided valuable insights into the functions of lamin A biogenesis and the roles of individual A-type lamins during tissue development. This review groups these LMNA-related mouse models into three categories: null mutants, point mutants, and progeroid mutants. We compare their phenotypes and discuss their potential implications in laminopathies and aging. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
    Aging cell 10/2012; 12(1). DOI:10.1111/acel.12021 · 6.34 Impact Factor
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