Increased expression of the Hutchinson–Gilford progeria syndrome truncated lamin A transcript during cell aging

Rodríguez, Sofía; Coppedè, Fabio; Sagelius, Hanna; Eriksson, Maria

doi:10.1038/ejhg.2008.270

Cited by 109 publications

(117 citation statements)

References 31 publications

(39 reference statements)

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“…17 Prelamin AΔ90 was amplified with a specific combination of primers and probe. The sequences are respectively 5′-CGAGGATGAGGATGGAGATGA-3′ for forward primer; 5′-CAGGTCCCAGATTACATGATGCT-3′ for reverse primer (overlapping exons 10 and 12) and 5′-CACCACAGCCCCCAGA-3′ for the specific probe.…”

Section: Transcriptional Analysis and Real-time Quantitative Pcrmentioning

confidence: 99%

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

et al. 2015

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Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene encoding lamins A and C, and is associated with nuclear deformation and dysfunction. Hutchinson-Gilford progeria syndrome (HGPS) was the first premature aging syndrome linked to LMNA mutation and its molecular bases have been deeply investigated. It is due to a recurrent de novo mutation leading to aberrant splicing and the production of a truncated and toxic nuclear lamin A precursor (prelamin AΔ50), also called progerin. In this work and based on the literature data, we propose to distinguish two main groups of premature aging laminopathies: (1) HGPS and HGP-like syndromes, which share clinical features due to hampered processing and intranuclear toxic accumulation of prelamin A isoforms; and (2) APS (atypical progeria syndromes), due to dominant or recessive missense mutations affecting lamins A and C. Among HGPS-like patients, several deleted prelamin A transcripts (prelamin AΔ50, AΔ35 and AΔ90) have been described. The purpose of this work was to characterize those transcripts in eight patients affected with HGP-like rare syndromes. When fibroblasts were available, the relationships between the presence and ratios of these transcripts and other parameters were studied, aiming to increase our understanding of genotype-phenotype relationships in HGPS-like patients. Altogether our results evidence that progerin accumulation is the major pathogenetic mechanism responsible for HGP-like syndromes due to mutations near the donor splice site of exon 11.

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Section: Transcriptional Analysis and Real-time Quantitative Pcrmentioning

confidence: 99%

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

et al. 2015

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“…This mutation activates a cryptic splice site that results in aberrant splicing of the lamin A transcript (Eriksson et al ., 2003). Interestingly, it has been shown that the products of this aberrant splicing, the truncated transcript and resultant protein (named progerin), increase in number with aging in HGPS (Goldman et al ., 2004; Cao et al ., 2007; Rodriguez et al ., 2009). In addition, several reports have found progerin, and increasing levels of progerin, in normal cells over the course of normal aging (Scaffidi & Misteli, 2006; McClintock et al ., 2007; Cao et al ., 2007; Rodriguez et al ., 2009), which suggests a similar genetic mechanism in HGPS and normal aging.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, it has been shown that the products of this aberrant splicing, the truncated transcript and resultant protein (named progerin), increase in number with aging in HGPS (Goldman et al ., 2004; Cao et al ., 2007; Rodriguez et al ., 2009). In addition, several reports have found progerin, and increasing levels of progerin, in normal cells over the course of normal aging (Scaffidi & Misteli, 2006; McClintock et al ., 2007; Cao et al ., 2007; Rodriguez et al ., 2009), which suggests a similar genetic mechanism in HGPS and normal aging. Moreover, genome‐scale expression profiling in cells from HGPS patients, as well as in physiological aging, has revealed widespread transcriptional misregulation in multiple mammalian tissues (Ly et al ., 2000; Csoka et al ., 2004; Zahn et al ., 2007; Scaffidi & Misteli, 2008; Cao et al ., 2011; McCord et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

et al. 2015

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SummaryAlternative splicing (AS) is a key regulatory mechanism for the development of different tissues; however, not much is known about changes to alternative splicing during aging. Splicing events may become more frequent and widespread genome‐wide as tissues age and the splicing machinery stringency decreases. Using skin, skeletal muscle, bone, thymus, and white adipose tissue from wild‐type C57BL6/J male mice (4 and 18 months old), we examined the effect of age on splicing by AS analysis of the differential exon usage of the genome. The results identified a considerable number of AS genes in skeletal muscle, thymus, bone, and white adipose tissue between the different age groups (ranging from 27 to 246 AS genes corresponding to 0.3–3.2% of the total number of genes analyzed). For skin, skeletal muscle, and bone, we included a later age group (28 months old) that showed that the number of alternatively spliced genes increased with age in all three tissues (P < 0.01). Analysis of alternatively spliced genes across all tissues by gene ontology and pathway analysis identified 158 genes involved in RNA processing. Additional analysis of AS in a mouse model for the premature aging disease Hutchinson–Gilford progeria syndrome was performed. The results show that expression of the mutant protein, progerin, is associated with an impaired developmental splicing. As progerin accumulates, the number of genes with AS increases compared to in wild‐type skin. Our results indicate the existence of a mechanism for increased AS during aging in several tissues, emphasizing that AS has a more important role in the aging process than previously known.

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“…3 IB) [90]. Progerin is also expressed sporadically in healthy individuals at low levels, and accumulates in old age [91]. It seems that progeroid syndrome is rather caused by the retention of farnesyl lipid than by the retention of the last 15 amino acids of the protein.…”

Section: Progeroid Syndromementioning

confidence: 99%

Laminopathies: The molecular background of the disease and the prospects for its treatment

Zaremba-Czogalla

Dubińska–Magiera

Rzepecki

2011

Cellular and Molecular Biology Letters

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phone: +48 71 375 63 08Abbreviations used: ADLD -adult-onset autosomal dominant leukodystrophy; APLacquired partial lipodystrophy; CMD1A -dilated cardiomyopathy 1A with conduction defect; CMT2B1 Charcot-Marie-Tooth disease type 2B1; DMD -Duchenne muscular dystrophy; EDMD -autosomal dominant Emery-Dreifuss muscular dystrophy; ERKextracellular signal-regulated kinase; GL -generalized lipodystrophy; FPLD -Dunnigan familial partial lipodystrophy; HGPS -Hutchinson Gilford progeria syndrome; INMinner nuclear membrane; JNK -c-Jun NH(2)-terminal kinase; LAP -lamina-associated polypeptide; LBR -p58 protein, lamin B receptor, 3 beta-hydroxysterol D14-reductase;LGMDB1 -limb-girdle muscular dystrophy type 1B; LINC -linker of the nucleoskeleton and cytoskeleton; LMNA -gene encoding A/C type lamins; MAD -mandibuloacral dysplasia; NE -nuclear envelope; PPARγ -peroxisome proliferator-activated receptor γ; pRB -retinoblastoma protein; ZMPSTE24/FACE1 -zinc metalloproteinase STE 24 homology Review LAMINOPATHIES: THE MOLECULAR BACKGROUND OF THE DISEASE AND THE PROSPECTS FOR ITS TREATMENTMAGDALENA ZAREMBA-CZOGALLA, MAGDA DUBIŃSKA-MAGIERA and RYSZARD RZEPECKI* Laboratory of Nuclear Proteins, Faculty of Biotechnology, University of Wrocław, ul. Przybyszewskiego 63/77, 51-148 Wroclaw, PolandAbstract: Laminopathies are rare human degenerative disorders with a wide spectrum of clinical phenotypes, associated with defects in the main protein components of the nuclear envelope, mostly in the lamins. They include systemic disorders and tissue-restricted diseases. Scientists have been trying to explain the pathogenesis of laminopathies and find an efficient method for treatment for many years. In this review, we discuss the current state of knowledge about laminopathies, the molecular mechanisms behind the development of particular phenotypes, and the prospects for stem cell and/or gene therapy treatments.

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Increased expression of the Hutchinson–Gilford progeria syndrome truncated lamin A transcript during cell aging

Cited by 109 publications

References 31 publications

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

Laminopathies: The molecular background of the disease and the prospects for its treatment

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