Lipodystrophy-Linked
            <i>LMNA</i>
            p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction

Bidault, Guillaume; Garcia, M.; Vantyghem, Marie-Christine; Ducluzeau, Pierre-Henri; Morichon, Romain; Thiyagarajah, Keerthihan Keerthihan; Moritz, Sylviane; Capeau, Jacqueline; Vigouroux, Corinne; Béréziat, Véronique

doi:10.1161/atvbaha.113.301933

Cited by 69 publications

(63 citation statements)

References 52 publications

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“…The increased UPRmt is correlated with longer lifespan in mice and in Caenorhabditis elegans [345]. One of the genes activated by the UPRmt is CHOP, also involved in the ER unfolding protein response [346], and activated in cells bearing R482W mutant lamin A [347]. Mitochondria and ER domains interact in MAM (Mitochondria-associated membranes), that represent highly specialized platforms involved in several functions [348] among them NFB activation and autophagy [349].…”

Section: Mitochondria Endoplasmic Reticulum Oxidative Stress and Numentioning

confidence: 99%

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Cau

Navarro

Harhouri

et al. 2014

Seminars in Cell & Developmental Biology

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Lamin A-related progeroid syndromes are genetically determined, extremely rare and severe. In the past ten years, our knowledge and perspectives for these diseases has widely progressed, through the progressive dissection of their pathophysiological mechanisms leading to precocious and accelerated aging, from the genes mutations discovery until therapeutic trials in affected children. A-type lamins are major actors in several structural and functional activities at the nuclear periphery, as they are major components of the nuclear lamina. However, while this is usually poorly considered, they also play a key role within the rest of the nucleoplasm, whose defects are related to cell senescence. Although nuclear shape and nuclear envelope deformities are obvious and visible events, nuclear matrix disorganization and abnormal composition certainly represent the most important causes of cell defects with dramatic pathological consequences. Therefore, lamin-associated diseases should be better referred as laminopathies instead of envelopathies, this later being too restrictive, considering neither the key structural and functional roles of soluble lamins in the entire nucleoplasm, nor the nuclear matrix contribution to the pathophysiology of lamin-associated disorders and in particular in defective lamin A processing-associated aging diseases. Based on both our understanding of pathophysiological mechanisms and the biological and clinical consequences of progeria and related diseases, therapeutic trials have been conducted in patients and were terminated less than 10 years after the gene discovery, a quite fast issue for a genetic disease. Pharmacological drugs have been repurposed and used to decrease the toxicity of the accumulated, unprocessed and truncated prelaminA in progeria. To date, none of them may be considered as a cure for progeria and these clinical strategies were essentially designed toward reducing a subset of the most dramatic and morbid features associated to progeria. New therapeutic strategies under study, in particular targeting the protein expression pathway at the mRNA level, have shown a remarkable efficacy both in vitro in cells and in vivo in mice models. Strategies intending to clear the toxic accumulated proteins from the nucleus are also under evaluation. However, although exceedingly rare, improving our knowledge of genetic progeroid syndromes and searching for innovative and efficient therapies in these syndromes is of paramount importance as, even before they can be used to save lives, they may significantly (i) expand the affected childrens' lifespan and preserve their quality of life; (ii) improve our understanding of aging-related disorders and other more common diseases; and (iii) expand our fundamental knowledge of physiological aging and its links with major physiological processes such as those involved in oncogenesis.

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Section: Mitochondria Endoplasmic Reticulum Oxidative Stress and Numentioning

confidence: 99%

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Cau

Navarro

Harhouri

et al. 2014

Seminars in Cell & Developmental Biology

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“…The level of adiponectin may also have had an effect on atherosclerosis in the present case. Therefore, because our patient was a woman with FPL and exhibited clustering of atherogenic risk factors, such as diabetes mellitus, hypertriglyceridemia and a low serum levels of adiponectin, it is conceivable that atherogenic risk factors and other factors, including unidentified causative genes affect the development of atherosclerosis, as we previously reported (30)(31)(32)(33)(34)(35).…”

Section: A B C D Ementioning

confidence: 90%

Primary Intestinal Follicular Lymphoma and Premature Atherosclerosis in a Japanese Diabetic Patient with Atypical Familial Partial Lipodystrophy

Iwanishi¹,

Kusakabe

Washiyama³

et al. 2014

Intern. Med.

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We experienced a case of primary intestinal follicular lymphoma and premature atherosclerosis in a diabetic patient with familial partial lipodystrophy (FPL) that was detected when the patient was evaluated for laparoscopic sleeve gastrectomy (LSG). As FPL is generally considered to be rare, FPL is often underdiagnosed, especially in obese patients. Therefore, the prevalence of FPL is higher than previous estimates. Our case illustrates that clinicians should perform screening for atherosclerosis and malignancy at the preoperative evaluation and may need to perform metabolic surgery earlier to prevent the development of excess truncal fat, complicated diabetes and atherosclerosis in patients with FPL.

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“…63 To evaluate whether p.R482W had a direct effect on vascular biology leading to early atherosclerosis that is prevalent in FPLD2, Bidault et al examined p.R482W-prelamin-A overexpression in human coronary artery endothelial cells. 64 In transduced endothelial cells, they found that exogenous wild-type-prelamin-A was correctly processed and localized. In contrast, p.R482W-prela- R482W is associated with interiorization of the mesodermal regulator T/Brachyury locus relative to normal fibroblasts, consistent with increasing susceptibility to activation of the locus.…”

Section: Lipodystrophy Variants and Lamin A Dysfunctionmentioning

confidence: 99%

Complex effects of laminopathy mutations on nuclear structure and function

Hegele

2018

Clinical Genetics

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The nuclear lamins are important members of the intermediate filament (IF) family of proteins, involved in structural support and regulation of the nuclear lamina. Different mutations in various members of these type V IF proteins produce a staggering range of human disease phenotypes, which collectively have been termed “laminopathies.” Compelling examples are the wide range of inherited disorders that result from rare variants in LMNA encoding lamin A/C. These laminopathies include skeletal and cardiac muscle disorders, neuropathies, multisystem progeroid disorders, and lipodystrophies, of which the latter are associated with several metabolic complications. Functions of lamin A/C that have been shown to be compromised by distinct mutations in LMNA include loss of nuclear structural integrity, altered interaction with transcription factors, and changes to post‐translational processing of pre‐lamins. Recently, evidence has emerged that certain LMNA mutations, such as those causing partial lipodystrophy, alter the interaction between chromatin and lamin A, in turn affecting the spatial orientation and distribution of chromatin within the nucleus. Because chromatin organization is exquisitely tied to global patterns of gene expression, the findings suggest a novel mechanism to explain the tissue‐specific impact of a subset of laminopathy‐associated LMNA mutations.

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Lipodystrophy-Linked LMNA p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction

Cited by 69 publications

References 52 publications

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Primary Intestinal Follicular Lymphoma and Premature Atherosclerosis in a Japanese Diabetic Patient with Atypical Familial Partial Lipodystrophy

Complex effects of laminopathy mutations on nuclear structure and function

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