Reduced adiponectin and HDL cholesterol without elevated C-reactive protein: Clues to the biology of premature atherosclerosis in Hutchinson-Gilford Progeria Syndrome

Gordon, Leslie B.; Harten, Ingrid A.; Patti, Mary Elizabeth; Lichtenstein, Alice H.

doi:10.1016/j.jpeds.2004.10.064

Cited by 78 publications

(60 citation statements)

References 40 publications

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“…The generally held assumption has been that the vascular occlusions are due to atherosclerosis. However, plasma cholesterol levels are normal in individuals with HGPS, and some characteristics of the vessel wall biology in individuals with HGPS are different from those of run-of-the-mill atherosclerosis (65,66). Thus, it is possible, and perhaps likely, that the vascular occlusions in HGPS are not due to classical atherosclerosis.…”

Section: Figurementioning

confidence: 99%

Laminopathies and the long strange trip from basic cell biology to therapy

Worman

Fong²,

Muchir³

et al. 2009

J. Clin. Invest.

234

239

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The main function of the nuclear lamina, an intermediate filament meshwork lying primarily beneath the inner nuclear membrane, is to provide structural scaffolding for the cell nucleus. However, the lamina also serves other functions, such as having a role in chromatin organization, connecting the nucleus to the cytoplasm, gene transcription, and mitosis. In somatic cells, the main protein constituents of the nuclear lamina are lamins A, C, B1, and B2. Interest in the nuclear lamins increased dramatically in recent years with the realization that mutations in LMNA, the gene encoding lamins A and C, cause a panoply of human diseases ("laminopathies"), including muscular dystrophy, cardiomyopathy, partial lipodystrophy, and progeroid syndromes. Here, we review the laminopathies and the long strange trip from basic cell biology to therapeutic approaches for these diseases.The nuclear lamina is an intermediate filament (IF) network composed of proteins called lamins and is part of the nuclear envelope of all somatic cells. For many years, research on the nuclear lamina was the domain of a relatively small group of cell biologists working on nuclear structure and mitosis. In the past decade, however, interest in the nuclear lamina has exploded with the discovery that mutations in the genes encoding lamins and associated nuclear envelope proteins cause a diverse range of human diseases. The mechanisms by which abnormalities in the nuclear lamina cause distinct human diseases (known as laminopathies) involving different tissues and organ systems have remained obscure. This review provides a general introduction to the nuclear lamins, focusing on "lacunae" in our understanding of these proteins. We focus on work in mammals but recognize that important insights regarding lamins have originated from studies of a number of other organisms (in particular, Xenopus, Drosophila, and Caenorhabditis elegans). We also discuss mechanisms by which mutations in lamin A/C (LMNA), the gene that encodes lamins A and C, might cause disease as well as potential therapeutic interventions for laminopathies. The nuclear envelope and nuclear laminaThe nuclear lamina, an IF network. The nuclear envelope, which is composed of nuclear membranes, nuclear pore complexes, and the nuclear lamina, separates the nucleus from the cytoplasm. The nuclear lamina is a meshwork of IF proteins known as lamins and is localized primarily on the inner aspect of the inner nuclear membrane (1-4) (Figure 1). In vertebrates, lamins have molecular masses of 60-80 kDa and generally have been divided into two groups, A type and B type, based on differences in isoelectric points (5).We now know that, in humans, three genes encode nuclear lamins (Figure 1). LMNA on chromosome 1 encodes the A-type lamins, with lamins A and C being the main isoforms in somatic cells (6). Lamins A and C are produced by alternative splicing, and the first 566 amino acids of the two proteins are identical. Lamin C has 6 unique amino acids at its carboxyl terminus, while prelamin A, the prec...

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Section: Figurementioning

confidence: 99%

Laminopathies and the long strange trip from basic cell biology to therapy

Worman

Fong²,

Muchir³

et al. 2009

J. Clin. Invest.

234

239

View full text Add to dashboard Cite

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“…2 Gordon also reported decreased HDL and adiponectin levels as children with HGPS age, whereas total cholesterol, C-reactive protein, triglycerides, and LDL all remained normal in HGPS, the same as in controls. 12 As discussed further below, HGPS is caused by single base change of a C to a T in position 608 of a gene known as LMNA. The profound cardiovascular phenotype in HGPS individuals has been reproduced in a mouse model of HGPS, a transgenic line that contains this human mutant G608G LMNA gene inserted through a BAC clone.…”

Section: Diseasementioning

confidence: 99%

Mechanisms of Cardiovascular Disease in Accelerated Aging Syndromes

Capell

Collins

Nabel

2007

Circulation Research

122

101

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Abstract-In the past several years, remarkable progress has been made in the understanding of the mechanisms of premature aging. These rare, genetic conditions offer valuable insights into the normal aging process and the complex biology of cardiovascular disease. Many of these advances have been made in the most dramatic of these disorders, Hutchinson-Gilford progeria syndrome. Although characterized by features of normal aging such as alopecia, skin wrinkling, and osteoporosis, patients with Hutchinson-Gilford progeria syndrome are affected by accelerated, premature arteriosclerotic disease that leads to heart attacks and strokes at a mean age of 13 years. In this review, we highlight recent advances in the biology of premature aging uncovered in Hutchinson-Gilford progeria syndrome and other accelerated aging syndromes, advances that provide insight into the mechanisms of cardiovascular diseases ranging from atherosclerosis to arrhythmias. (Circ Res. 2007;101:13-26.)Key Words: premature aging Ⅲ progeria Ⅲ Werner syndrome Ⅲ genome instability P remature aging syndromes, such as Hutchinson-Gilford progeria syndrome (HGPS), result in fatal cardiovascular disease. 1 Cardiovascular features of HGPS share striking similarities and dissimilarities with atherosclerosis. In this review, we present recent discoveries in this burgeoning scientific field, focus on cardiovascular aspects, and describe how developments may lead not only to new treatments and therapies for these rare conditions but also to new mechanistic insights into the biology of cardiovascular diseases, such as atherosclerosis and arrhythmias.

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“…The average age of death in HGPS is 12 to 15 years, usually due to artherosclerosis resulting in myocardial infarction or stroke [44]. Artherosclerosis in the HGPS patients does not appear to be linked to abnormal systemic lipid levels [45], but might be linked to smooth muscle depletion in atherosclerotic aortas [46]. Also, HGPS individuals do not show any increase in tumor susceptibility, cataract formation, or cognitive degeneration, features often associated with normal aging.…”

Section: The A-type Laminopathiesmentioning

confidence: 99%

Mouse models of the laminopathies

Stewart

Kozlov

Fong

et al. 2007

Experimental Cell Research

107

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The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A-type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner's syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the Atype lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease.

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Reduced adiponectin and HDL cholesterol without elevated C-reactive protein: Clues to the biology of premature atherosclerosis in Hutchinson-Gilford Progeria Syndrome

Cited by 78 publications

References 40 publications

Laminopathies and the long strange trip from basic cell biology to therapy

Laminopathies and the long strange trip from basic cell biology to therapy

Mechanisms of Cardiovascular Disease in Accelerated Aging Syndromes

Mouse models of the laminopathies

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