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Colin L. Stewart - One of the best experts on this subject based on the ideXlab platform.
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lamin a c maintains exocrine pancreas homeostasis by regulating stability of rb and activity of e2f
Gastroenterology, 2018Co-Authors: Jared S Elenbaas, Colin L. Stewart, Elif A. Oral, Juliana Bragazzi Cunha, Rodrigo Azuerodajud, Bradley Nelson, John A Williams, Bishr M OmaryAbstract:Lamins have important roles in nuclear structure and cell signaling. Several diseases are associated with mutations in the lamin A/C gene (LMNA in humans). Patients with familial partial lipodystrophy caused by LMNA mutations develop pancreatitis, but lamin function in the pancreas and how these mutations affect pancreatic regulation are unknown. We generated mice with inducible exocrine pancreas-specific disruption of LMNA and showed that LMNA is lost from most exocrine pancreas cells. LMNA-knockout pancreata develop endoplasmic reticulum stress with loss of acinar cell markers, increased autophagy, apoptosis, and cell proliferation, compared to CreERT2– mice (littermate controls). Disruption of LMNA led to a phenotype that resembled chronic pancreatitis, with increased Sirius Red staining and α–smooth muscle actin in male LMNA-knockout mice compared to littermate males, but not in female mice. LMNA-knockout pancreata have reduced levels of RB and activation of E2F, based on increased expression of E2F target genes. Therefore, lamins maintain pancreatic homeostasis by regulating RB stability and E2F activity.
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Behavioral and molecular exploration of the AR-CMT2A mouse model LMNA (R298C/R298C).
NeuroMolecular Medicine, 2012Co-Authors: Yannick Poitelon, Serguei Kozlov, Jerôme Devaux, Jean-michel Vallat, Marc Jamon, Pierre L. Roubertoux, Sitraka Rabarimeriarijaona, Cécile Baudot, Tarik Hamadouche, Colin L. StewartAbstract:In 2002, we identified LMNA as the first gene responsible for an autosomal recessive axonal form of Charcot-Marie-Tooth disease, AR-CMT2A. All patients were found to be homozygous for the same mutation in the LMNA gene, p.Arg298Cys. In order to investigate the physiopathological mechanisms underlying AR-CMT2A, we have generated a knock-in mouse model for the LMNA p.Arg298Cys mutation. We have explored these mice through an exhaustive series of behavioral tests and histopathological analyses, but were not able to find any peripheral nerve phenotype, even at 18 months of age. Interestingly at the molecular level, however, we detect a downregulation of the LMNA gene in all tissues tested from the homozygous knock-in mouse LMNA (R298C/R298C) (skeletal muscle, heart, peripheral nerve, spinal cord and cerebral trunk). Importantly, we further reveal a significant upregulation of Pmp22, specifically in the sciatic nerves of LMNA (R298C/R298C) mice. These results indicate that, despite the absence of a perceptible phenotype, abnormalities exist in the peripheral nerves of LMNA (R298C/R298C) mice that are absent from other tissues. Although the mechanisms leading to deregulation of Pmp22 in LMNA (R298C/R298C) mice are still unclear, our results support a relation between LMNA and Pmp22 and constitute a first step toward understanding AR-CMT2A physiopathology.
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Behavioral and Molecular Exploration of the AR-CMT2A Mouse Model LMNA ^ R298C/R298C
NeuroMolecular Medicine, 2012Co-Authors: Yannick Poitelon, Serguei Kozlov, Jerôme Devaux, Jean-michel Vallat, Marc Jamon, Pierre L. Roubertoux, Sitraka Rabarimeriarijaona, Cécile Baudot, Tarik Hamadouche, Colin L. StewartAbstract:In 2002, we identified LMNA as the first gene responsible for an autosomal recessive axonal form of Charcot-Marie-Tooth disease, AR-CMT2A. All patients were found to be homozygous for the same mutation in the LMNA gene, p.Arg298Cys. In order to investigate the physiopathological mechanisms underlying AR-CMT2A, we have generated a knock-in mouse model for the LMNA p.Arg298Cys mutation. We have explored these mice through an exhaustive series of behavioral tests and histopathological analyses, but were not able to find any peripheral nerve phenotype, even at 18 months of age. Interestingly at the molecular level, however, we detect a downregulation of the LMNA gene in all tissues tested from the homozygous knock-in mouse LMNA ^ R298C/R298C (skeletal muscle, heart, peripheral nerve, spinal cord and cerebral trunk). Importantly, we further reveal a significant upregulation of Pmp22, specifically in the sciatic nerves of LMNA ^ R298C/R298C mice. These results indicate that, despite the absence of a perceptible phenotype, abnormalities exist in the peripheral nerves of LMNA ^ R298C/R298C mice that are absent from other tissues. Although the mechanisms leading to deregulation of Pmp22 in LMNA ^ R298C/R298C mice are still unclear, our results support a relation between LMNA and Pmp22 and constitute a first step toward understanding AR-CMT2A physiopathology.
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Characterization of adiposity and metabolism in LMNA-deficient mice.
Biochemical and Biophysical Research Communications, 2002Co-Authors: Dedra A. Cutler, Teresa Sullivan, Bernice Marcus-samuels, Colin L. Stewart, Marc L. ReitmanAbstract:Abstract Dunnigan's Familial Partial Lipodystrophy (FPLD) is an autosomal dominant disease characterized by regional fat loss and insulin resistance. FPLD is caused by mutations in the LMNA gene, which encodes intermediate filaments of the nuclear lamina. Different LMNA mutations cause Emery–Dreifuss muscular dystrophy and/or a dilated cardiomyopathy. It is not known how LMNA mutations cause any of the disease phenotypes. Here we measure physical and metabolic characteristics of LMNA−/− and +/− mice to determine their usefulness as models for FPLD. LMNA−/− mice, which die prematurely of muscular dystrophy, have little fat, but do not show the insulin resistance characteristic of FPLD. LMNA+/− mice, despite treatment with a high fat diet, do not have decreased fat stores or metabolic features of FPLD. We also show, in mice, that LMNA transcripts are expressed at high levels in muscle and adipose tissue, but do not vary by body region or sex. In conclusion, LMNA+/− and −/− mice do not mimic Dunnigan's FPLD, and differential expression of lamins A and C does not appear to contribute to sex- or tissue-specific LMNA phenotypes.
Steve D. Wilton - One of the best experts on this subject based on the ideXlab platform.
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Antisense oligonucleotide induction of progerin in human myogenic cells
PLoS ONE, 2014Co-Authors: Yue-bei Luo, Frank L. Mastaglia, Steve D. Wilton, C. Mitrpant, Russell D. Johnsen, Sue Fletcher, Abbie M. AdamsAbstract:We sought to use splice-switching antisense oligonucleotides to produce a model of accelerated ageing by enhancing expression of progerin, translated from a mis-spliced lamin A gene (LMNA) transcript in human myogenic cells. The progerin transcript (LMNA Δ150) lacks the last 150 bases of exon 11, and is translated into a truncated protein associated with the severe premature ageing disease, Hutchinson-Gilford progeria syndrome (HGPS). HGPS arises from de novo mutations that activate a cryptic splice site in exon 11 of LMNA and result in progerin accumulation in tissues of mesodermal origin. Progerin has also been proposed to play a role in the ‘natural’ ageing process in tissues. We sought to test this hypothesis by producing a model of accelerated muscle ageing in human myogenic cells. A panel of splice-switching antisense oligonucleotides were designed to anneal across exon 11 of the LMNA pre-mRNA, and these compounds were transfected into primary human myogenic cells. RT-PCR showed that the majority of oligonucleotides were able to modify LMNA transcript processing. Oligonucleotides that annealed within the 150 base region of exon 11 that is missing in the progerin transcript, as well as those that targeted the normal exon 11 donor site induced the LMNA Δ150 transcript, but most oligonucleotides also generated variable levels of LMNA transcript missing the entire exon 11. Upon evaluation of different oligomer chemistries, the morpholino phosphorodiamidate oligonucleotides were found to be more efficient than the equivalent sequences prepared as oligonucleotides with 2′-O-methyl modified bases on a phosphorothioate backbone. The morpholino oligonucleotides induced nuclear localised progerin, demonstrated by immunostaining, and morphological nuclear changes typical of HGPS cells. We show that it is possible to induce progerin expression in myogenic cells using splice-switching oligonucleotides to redirect splicing of LMNA. This may offer a model to investigate the role of progerin in premature muscle ageing.
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Normal and aberrant splicing of LMNA
Journal of Medical Genetics, 2014Co-Authors: Yue-bei Luo, Frank L. Mastaglia, Steve D. WiltonAbstract:The LMNA gene gives rise to at least three isoforms (lamin A, C, lamin AΔ10) as a result of normal alternative splicing, regulated by cis- and trans-acting regulatory factors, as well as the 5′ and 3′ untranslated regions of the gene. The two main isoforms, lamin A and C, are constitutive components of the fibrous nuclear lamina and have diverse physiological roles, ranging from mechanical nuclear membrane maintenance to gene regulation. The clinical spectrum of diseases (called ‘laminopathies’) caused by LMNA mutations is broad, including at least eight well-characterised phenotypes, some of which are confined to the skeletal muscles or skin, while others are multisystemic. This review discusses the different alternatively spliced isoforms of LMNA and the regulation of LMNA splicing, as well as the subgroup of mutations that affect splicing of LMNA pre-mRNA, and also seeks to bridge the mis-splicing of LMNA at transcript level and the resulting clinical phenotypes. Finally, we discuss the manipulation of LMNA splicing by splice-switching antisense oligonucleotides and its therapeutic potential for the treatment of some laminopathies.
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Investigation of age-related changes in LMNA splicing and expression of progerin in human skeletal muscles
International journal of clinical and experimental pathology, 2013Co-Authors: Yue-bei Luo, Frank L. Mastaglia, C. Mitrpant, Russell D. Johnsen, Victoria A. Fabian, Sue Fletcher, Steve D. WiltonAbstract:Age-related changes in splice-forms of LMNA, which encodes the nuclear lamina proteins lamin A/C, have not been investigated in skeletal muscle. In the rare premature ageing disease, Hutchinson-Gilford progeria syndrome (HGPS), de novo point mutations in LMNA activate a cryptic splice site in exon 11, resulting in a 150 base deletion in LMNA mRNA and accumulation of a truncated protein isoform, progerin. The LMNA ∆150 progerin transcript has also been found in trace quantities in tissues of healthy people and its implication in ‘natural’ ageing has been proposed. We therefore investigated the expression of progerin and lamin A/C in normal human and mouse skeletal muscles of different ages. LMNA ∆150 was detected in most muscle samples from healthy individuals aged 16-71 years, but was not present in any mouse muscle samples up to the age of 18 months. Real time qPCR of human muscle samples showed that there was an age-related increase in both the full length lamin A and LMNA ∆150 transcripts, whereas their protein levels did not change significantly with age. These findings indicate that there is a basal level of mis-splicing during LMNA expression that does not change with ageing in human muscle, but at levels that do not result in increased aberrant protein. The significance of these findings in the pathophysiology of muscle ageing is uncertain and warrants further investigation.
Gisèle Bonne - One of the best experts on this subject based on the ideXlab platform.
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Consequences of LMNA Exon 4 Mutations in Myoblast Function.
Cells, 2020Co-Authors: Déborah Gómez-domínguez, Gisèle Bonne, Anne T. Bertrand, Carolina Epifano, Fernando De Miguel, Albert García Castaño, Borja Vilaplana-martí, Alberto Martín, Sandra Amarilla-quintana, Javier Ramón-azcónAbstract:Laminopathies are causally associated with mutations on the Lamin A/C gene (LMNA). To date, more than 400 mutations in LMNA have been reported in patients. These mutations are widely distributed throughout the entire gene and are associated with a wide range of phenotypes. Unfortunately, little is known about the mechanisms underlying the effect of the majority of these mutations. This is the case of more than 40 mutations that are located at exon 4. Using CRISPR/Cas9 technology, we generated a collection of LMNA exon 4 mutants in mouse C2C12 myoblasts. These cell models included different types of exon 4 deletions and the presence of R249W mutation, one of the human variants associated with a severe type of laminopathy, LMNA-associated congenital muscular dystrophy (L-CMD). We characterized these clones by measuring their nuclear circularity, myogenic differentiation capacity in 2D and 3D conditions, DNA damage, and levels of p-ERK and p-AKT (phosphorylated Mitogen-Activated Protein Kinase 1/3 and AKT serine/threonine kinase 1). Our results indicated that LMNA exon 4 mutants showed abnormal nuclear morphology. In addition, levels and/or subcellular localization of different members of the lamin and LINC (LInker of Nucleoskeleton and Cytoskeleton) complex were altered in all these mutants. Whereas no significant differences were observed for ERK and AKT activities, the accumulation of DNA damage was associated to the LMNA p.R249W mutant myoblasts. Finally, significant myogenic differentiation defects were detected in the LMNA exon 4 mutants. These results have key implications in the development of future therapeutic strategies for the treatment of laminopathies.
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Consequences of LMNA Exon 4 Mutations in Myoblast Function
2020Co-Authors: Déborah Gómez-domínguez, Gisèle Bonne, Anne T. Bertrand, Carolina Epifano, Fernando De Miguel, Albert García Castaño, Borja Vilaplana-martí, Alberto Martín, Sandra Amarilla-quintana, Javier Ramón-azcónAbstract:Laminopathies are causally associated with mutations on Lamin A gene (LMNA). To date, more than 400 mutations in LMNA have been reported in patients. These mutations are widely distributed throughout the entire gene and are associated with a wide range of phenotypes. Unfortunately, little is known about the mechanisms underlying the effect of the majority of these mutations. This is the case of more than 40 mutations that are located at exon 4. Using CRISPR/Cas9 technology, we have generated a collection of LMNA exon 4 mutants in mouse C2C12 myoblasts. These cell models include different types of exon 4 deletions and the presence of R249W mutation, one of the human variants associated with a severe type of laminopathy (LMNA-associated congenital muscular dystrophy). We have characterized these clones by measuring their nuclear circularity, myogenic differentiation capacity in 2D and 3D conditions, DNA damage, and p-ERK and p-AKT levels. Our results indicate that LMNA exon 4 mutants show abnormal nuclear morphology. In addition, levels and/or subcellular localization of different members of the lamin and LINC complex are altered in all these mutants. Whereas no significant differences were observed for ERK and AKT activities, the accumulation of DNA damage was associated to the LMNA p.R249W mutant myoblasts. Finally, significant myogenic differentiation defects were detected in the LMNA exon 4 mutants. These results have key implications in the development of future therapeutic strategies for the treatment of laminopathies.
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Activation of sarcolipin expression and altered calcium cycling in LMNA cardiomyopathy
Biochemistry and Biophysics Reports, 2020Co-Authors: Blanca Morales Rodriguez, Gisèle Bonne, Alejandro Domínguez-rodríguez, Jean-pierre Benitah, Florence Lefebvre, Thibaut Marais, Nathalie Mougenot, Philippe Beauverger, Véronique Briand, Ana-maria GomezAbstract:Cardiomyopathy caused by A-type lamins gene (LMNA) mutations (LMNA cardiomyopathy) is associated with dysfunction of the heart, often leading to heart failure. LMNA cardiomyopathy is highly penetrant with bad prognosis with no specific therapy available. Searching for alternative ways to halt the progression of LMNA cardiomyopathy, we studied the role of calcium homeostasis in the evolution of this disease. We showed that sarcolipin, an inhibitor of the sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA) was abnormally elevated in the ventricular cardiomyocytes of mutated mice compared with wild type mice, leading to an alteration of calcium handling. This occurs early in the progression of the disease, when the left ventricular function was not altered. We further demonstrated that down regulation of sarcolipin using adeno-associated virus (AAV) 9-mediated RNA interference delays cardiac dysfunction in mouse model of LMNA cardiomyopathy. These results showed a novel role for sarcolipin on calcium homeostasis in heart and open perspectives for future therapeutic interventions to LMNA cardiomyopathy.
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SMAD6 overexpression leads to accelerated myogenic differentiation of LMNA mutated cells
Scientific Reports, 2018Co-Authors: Alexandre Janin, Gisèle Bonne, Delphine Bauer, Francesca Ratti, Camille Valla, Anne Bertrand, Emilie Christin, Emilie Chopin, Nathalie Streichenberger, Vincent GacheAbstract:LMNA gene encodes lamins A and C, two major components of the nuclear lamina, a network of intermediate filaments underlying the inner nuclear membrane. Most of LMNA mutations are associated with cardiac and/or skeletal muscles defects. Muscle laminopathies include Emery-Dreifuss Muscular Dystrophy, Limb-Girdle Muscular Dystrophy 1B, LMNA-related Congenital Muscular Dystrophy and Dilated Cardiomyopathy with conduction defects. To identify potential alterations in signaling pathways regulating muscle differentiation in LMNA-mutated myoblasts, we used a previously described model of conditionally immortalized murine myoblasts: H-2K cell lines. Comparing gene expression profiles in wild-type and LMNA∆8–11 H-2K myoblasts, we identified two major alterations in the BMP (Bone Morphogenetic Protein) pathway: Bmp4 downregulation and Smad6 overexpression. We demonstrated that these impairments lead to LMNA∆8–11 myoblasts premature differentiation and can be rescued by downregulating Smad6 expression. Finally, we showed that BMP4 pathway defects are also present in myoblasts from human patients carrying different heterozygous LMNA mutations.
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N-acetyl cysteine alleviates oxidative stress and protects mice from dilated cardiomyopathy caused by mutations in nuclear A-type lamins gene
Human Molecular Genetics, 2018Co-Authors: Blanca Morales Rodriguez, Gisèle Bonne, Lara Khouzami, Valérie Decostre, Shaida Varnous, Vanja Pekovic-vaughan, Christopher Hutchison, Françoise Pecker, Antoine MuchirAbstract:Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is an anatomic and pathologic condition associated with muscular and electrical dysfunction of the heart, often leading to heart failure-related disability. There is currently no specific therapy available for patients that target the molecular pathophysiology of LMNA cardiomyopathy. We showed here an increase in oxidative stress levels in the hearts of mice carrying LMNA mutation, associated with a decrease of the key cellular antioxidant glutathione (GHS). Oral administration of N-acetyl cysteine, a GHS precursor, led to a marked improvement of GHS content, a decrease in oxidative stress markers including protein carbonyls and an improvement of left ventricular structure and function in a model of LMNA cardiomyopathy. Collectively, our novel results provide therapeutic insights into LMNA cardiomyopathy.
Irena Hausmanowa-petrusewicz - One of the best experts on this subject based on the ideXlab platform.
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Progeroid syndrome with scleroderma-like skin changes associated with homozygous R435C LMNA mutation.
American Journal of Medical Genetics Part A, 2009Co-Authors: Agnieszka Madej-pilarczyk, Michał Marchel, Ewa Szaluś, Stefania Jabłońska, Danuta Rosińska‐borkowska, Joanna Rękawek, Irena Hausmanowa-petrusewiczAbstract:Hutchinson–Gilford progeria is a rare genetic disorder resulting from mutations in the LMNA gene encoding lamin A/C. In addition to the classical phenotype usually caused by the 1824C>T mutation of LMNA, a number of atypical progeroid syndromes have been described. They have some distinct features, such as skeletal deformities or scleroderma-like skin changes. The underlying defect is usually a homozygous mutation of LMNA, or a combined defect of LMNA and another gene, for example, ZMPSTE-24. We present a 2-year-old girl born to consanguineous parents affected by progeroid syndrome with scleroderma-like skin changes. Genetic analysis revealed the homozygous LMNA mutation 1303C>T (R435C). The same heterozygous mutation was found in the patient's parents and 11 other family members. The progeroid syndrome in our patient shares the signs of two laminopathies: progeria and restrictive dermatopathy. Two other children in the family died at the age of 2 due to a disease similar to that in the proposita. On the basis of the family pedigree we presume that these children probably had the same homozygous LMNA mutation. Scleroderma-like skin changes in infants, associated with growth retardation and dysmorphic features, suggest premature aging syndrome, requiring genetic testing and counseling of asymptomatic carriers of LMNA mutations. © 2009 Wiley-Liss, Inc.
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Progeroid syndrome with scleroderma-like skin changes associated with homozygous R435C LMNA mutation.
American Journal of Medical Genetics Part A, 2009Co-Authors: Agnieszka Madej-pilarczyk, Danuta Rosińska-borkowska, Joanna Rekawek, Michał Marchel, Ewa Szaluś, Stefania Jabłońska, Irena Hausmanowa-petrusewiczAbstract:Hutchinson-Gilford progeria is a rare genetic disorder resulting from mutations in the LMNA gene encoding lamin A/C. In addition to the classical phenotype usually caused by the 1824C>T mutation of LMNA, a number of atypical progeroid syndromes have been described. They have some distinct features, such as skeletal deformities or scleroderma-like skin changes. The underlying defect is usually a homozygous mutation of LMNA, or a combined defect of LMNA and another gene, for example, ZMPSTE-24. We present a 2-year-old girl born to consanguineous parents affected by progeroid syndrome with scleroderma-like skin changes. Genetic analysis revealed the homozygous LMNA mutation 1303C>T (R435C). The same heterozygous mutation was found in the patient's parents and 11 other family members. The progeroid syndrome in our patient shares the signs of two laminopathies: progeria and restrictive dermatopathy. Two other children in the family died at the age of 2 due to a disease similar to that in the proposita. On the basis of the family pedigree we presume that these children probably had the same homozygous LMNA mutation. Scleroderma-like skin changes in infants, associated with growth retardation and dysmorphic features, suggest premature aging syndrome, requiring genetic testing and counseling of asymptomatic carriers of LMNA mutations.
Jacqueline Capeau - One of the best experts on this subject based on the ideXlab platform.
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LMNA mutations resulting in lipodystrophy and HIV protease inhibitors trigger vascular smooth muscle cell senescence and calcification: Role of ZMPSTE24 downregulation
Atherosclerosis, 2016Co-Authors: Pauline Afonso, Jacqueline Capeau, Martine Auclair, Franck Boccara, Marie-christine Vantyghem, Christine Katlama, Corinne Vigouroux, Martine Caron-debarleAbstract:Background Some LMNA mutations responsible for lipodystrophies, and some HIV-protease inhibitors (PIs) induce accumulation of farnesylated prelamin A and premature senescence in some cell types. Patients with LMNA mutations or under PI-based therapy suffer from early atherosclerosis. The metalloprotease ZMPSTE24 is the key enzyme in prelamin A maturation. Aim We studied whether altered expression of ZMPSTE24 could contribute to vascular cell dysfunction in response to LMNA mutations or PI treatments. Methods Protein expression of prelamin A and ZMPSTE24 were evaluated in patients' cells and in human cultured VSMCs. Oxidative stress, inflammation, senescence and transdifferentiation/calcification were evaluated in VSMCs. Results Fibroblasts from LMNA-mutated lipodystrophic patients (mutations R482W, D47Y or R133L) and peripheral blood mononuclear cells from PI-treated-HIV-infected patients expressed increased prelamin A and decreased ZMPSTE24, which was also observed in VSMCs overexpressing mutant LMNA or treated with PIs. These alterations correlated with oxidative stress, inflammation, senescence and calcification (all p < 0.05). ZMPSTE24 silencing in native VSMCs recapitulated the mutant LMNA- and PI-induced accumulation of farnesylated prelamin A, oxidative stress, inflammation, senescence and calcification. A negative regulator of ZMPSTE24, miRNA-141-3p, was enhanced in LMNA-mutated or PI-treated VSMCs. The farnesylation inhibitors pravastatin and FTI-277, or the antioxidant N-acetyl cysteine, partly restored ZMPSTE24 expression, and concomitantly decreased oxidative stress, inflammation, senescence, and calcification of PI-treated VSCMs. Conclusions ZMPSTE24 downregulation is a major contributor in VSMC dysfunctions resulting from LMNA mutations or PI treatments that could translate in early atherosclerosis at the clinical level. These novel pathophysiological mechanisms could open new therapeutic perspectives for cardiovascular aging.
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Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence
Cell Death and Differentiation, 2007Co-Authors: Maeva Caron, B. Donadille, H. Narbonne, Véronique Béréziat, Michel Laville, Bruno Guerci, Olivier Lascols, Martine Auclair, Christine Bodemer, Jacqueline CapeauAbstract:Lipodystrophic syndromes associated with mutations in LMNA, encoding A-type lamins, and with HIV antiretroviral treatments share several clinical characteristics. Nuclear alterations and prelamin A accumulation have been reported in fibroblasts from patients with LMNA mutations and adipocytes exposed to protease inhibitors (PI). As genetically altered lamin A maturation also results in premature ageing syndromes with lipodystrophy, we studied prelamin A expression and senescence markers in cultured human fibroblasts bearing six different LMNA mutations or treated with PIs. As compared to control cells, fibroblasts with LMNA mutations or treated with PIs had nuclear shape abnormalities and reduced proliferative activity that worsened with increasing cellular passages. They exhibited prelamin A accumulation, increased oxidative stress, decreased expression of mitochondrial respiratory chain proteins and premature cellular senescence. Inhibition of prelamin A farnesylation prevented cellular senescence and oxidative stress. Adipose tissue samples from patients with LMNA mutations or treated with PIs also showed retention of prelamin A, overexpression of the cell cycle checkpoint inhibitor p16 and altered mitochondrial markers. Thus, both LMNA mutations and PI treatment result in accumulation of farnesylated prelamin A and oxidative stress that trigger premature cellular senescence. These alterations could participate in the pathophysiology of lipodystrophic syndromes and lead to premature ageing complications.