<i>LMNA</i>‐associated cardiocutaneous progeria: An inherited autosomal dominant premature aging syndrome with late onset

Kane, Megan; Lindsay, Mark E.; Judge, Daniel P.; Barrowman, Jemima; Rhys, Colette ap; Simonson, Lisa; Dietz, Harry C.; Michaelis, Susan

doi:10.1002/ajmg.a.35971

Cited by 26 publications

(36 citation statements)

References 83 publications

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“…Given their common molecular bases linked to prelamin Adeficient processing, we propose to name this group of diseases "HGPS-like" syndromes. Conversely, a distinct group of premature aging syndromes called "Atypical Progeria Syndromes" (APS) are being delineated [177][178][179] (Fig. 2).…”

Section: Hgps and Rd Are Premature Aging Related Disordersmentioning

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: Hgps and Rd Are Premature Aging Related Disordersmentioning

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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“…Both HGS and WS have unique phenotypes with several overlapping clinical features. 2,7,[10][11][12][13] The analysis of our patient's LMNA gene revealed a heterozygous point mutation in exon 5, c.898G>A (p.D300N). 2 These patients have been diagnosed with APS or AWS.…”

Section: Discussionmentioning

confidence: 77%

First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygous LMNA mutation

Motegi

Yokoyama

Uchiyama

et al. 2014

The Journal of Dermatology

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Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a progeroid syndrome involving heterozygous mutations in the LMNA gene encoding the nuclear protein lamin A/C. We report the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). A 53-year-old Japanese man had a history of recurrent severe cardiovascular diseases as well as brain infarction and hemorrhages. Although our APS/AWS patient had overlapping features with Werner syndrome (WS), such as high-pitched voice, scleroderma, lipoatrophy and atherosclerosis, several cardinal features of WS, including short stature, premature graying/alopecia, cataract, bird-like face, flat feet, hyperkeratosis on the soles and diabetes mellitus, were absent. In immunofluorescence staining and electron microscopic analyses of the patient's cultured fibroblasts, abnormal nuclear morphology, an increase in small aggregation of heterochromatin and a decrease in interchromatin granules in nuclei of fibroblasts were observed, suggesting that abnormal nuclear morphology and chromatin disorganization may be associated with the pathogenesis of APS/AWS.

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“…Progerin accumulation is directly involved in the vascular disease associated with the syndrome [227]. FTase inhibition has proved to be beneficial for the alleviation of the condition [228,229]. In the clinical trials of progeric children, FTase inhibitor lonafarnib improved vascular function, bone structure, and audiological status [230].…”

Section: Farnesyltransferase (Protein Farnesyltransferase)mentioning

confidence: 99%

Enzymatic Targets in Atherosclerosis

Fuior¹,

Trusca²,

Roman³

et al. 2015

J Mol Genet Med

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Atherosclerosis, a prime cause of mortality across the developed societies, was targeted by diverse therapeutic strategies. These evolved in response to the complex etiology and evolution of the disease. Many enzymes are associated with atherosclerosis, either in the main stream of lipid biosynthesis and transport or in the collateral and intertwined pathways of oxidative stress, inflammation, vascular remodeling or chromatin stability and are therefore revised herein. Enzyme exploration led to important developments. At the beginning, there were the statins, derived as inhibitors of hydroxy-methyl-glutaryl CoA (HMG-CoA) reductase, currently used widely to decrease lipid levels. At the other end, the inhibitors of the recently discovered proprotein convertase subtilisin/kexin type 9 (PCSK9) are awaiting the validation in clinical trials with great hopes for the future. In between, one can find some palliatives, as aspirin, an inhibitor of cyclooxygenase (COX), but also many invalidated candidates. Classical pharmacological data and newer approaches, like genetic knockouts in murine atherosclerosis models, are reviewed in order to appreciate the involvement of a particular enzyme in atherogenesis. However, the pursuit of an efficacious drug has been long and, in many cases, disappointing. Conclusions can be drawn from the overview of both successes and failures, in a quest for the best.

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LMNA‐associated cardiocutaneous progeria: An inherited autosomal dominant premature aging syndrome with late onset

Cited by 26 publications

References 83 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

First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygous LMNA mutation

Enzymatic Targets in Atherosclerosis

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