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Annual Review of Physiology Feb 2018Aging, the main risk factor for cardiovascular disease (CVD), is becoming progressively more prevalent in our societies. A better understanding of how aging promotes CVD... (Review)
Review
Aging, the main risk factor for cardiovascular disease (CVD), is becoming progressively more prevalent in our societies. A better understanding of how aging promotes CVD is therefore urgently needed to develop new strategies to reduce disease burden. Atherosclerosis and heart failure contribute significantly to age-associated CVD-related morbimortality. CVD and aging are both accelerated in patients suffering from Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder caused by the prelamin A mutant progerin. Progerin causes extensive atherosclerosis and cardiac electrophysiological alterations that invariably lead to premature aging and death. This review summarizes the main structural and functional alterations to the cardiovascular system during physiological and premature aging and discusses the mechanisms underlying exaggerated CVD and aging induced by prelamin A and progerin. Because both proteins are expressed in normally aging non-HGPS individuals, and most hallmarks of normal aging occur in progeria, research on HGPS can identify mechanisms underlying physiological aging.
Topics: Aging; Animals; Cardiovascular Diseases; Cardiovascular System; Humans; Progeria; Vascular Calcification
PubMed: 28934587
DOI: 10.1146/annurev-physiol-021317-121454 -
Science Translational Medicine Feb 2013A clinical trial of a protein farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here,... (Review)
Review
A clinical trial of a protein farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here, we discuss the mutation that causes HGPS, the rationale for inhibiting protein farnesyltransferase, the potential limitations of this therapeutic approach, and new potential strategies for treating the disease.
Topics: Animals; Cell Nucleus Shape; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Lamins; Progeria; Protein Prenylation
PubMed: 23390246
DOI: 10.1126/scitranslmed.3005229 -
Development, Growth & Differentiation Jan 2016Progeria is a devastating disorder in which patients exhibit signs of premature aging. The most well-known progeroid syndromes include Hutchinson-Gilford Progeria... (Review)
Review
Progeria is a devastating disorder in which patients exhibit signs of premature aging. The most well-known progeroid syndromes include Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner Syndrome (WS). While HGPS and WS are rare, they often result in severe age-associated complications starting in the early developmental period or after the pubertal growth spurt during adolescence, respectively. In addition, patients with HGPS ultimately die of diseases normally seen in the elderly population, with stroke and myocardial infarction as the leading causes of death. Many WS patients develop similar cardiovascular complications but also have an increased predisposition to developing multiple rare malignancies. These premature aging disorders, as well as animal and cell culture models that recapitulate these diseases, have provided insight into the genetics and cellular pathways that underlie these human conditions and have also uncovered possible mechanisms behind normal aging. Here we discuss the history, the types of progeria, and the various pathophysiological mechanisms that drive these diseases. We also address recent medical advances and treatment modalities for patients with progeria.
Topics: Adolescent; Adolescent Development; Animals; Female; Humans; Male; Progeria; Puberty; Werner Syndrome
PubMed: 26691051
DOI: 10.1111/dgd.12251 -
Ryoikibetsu Shokogun Shirizu 1996
Review
Topics: Adolescent; Adult; Child; Coronary Disease; Humans; Progeria
PubMed: 9048032
DOI: No ID Found -
Nucleus (Austin, Tex.) Dec 2019Lamin A, a product of the LMNA gene, is an essential nuclear envelope component in most differentiated cells. Mutations in LMNA have been linked to premature aging... (Review)
Review
Lamin A, a product of the LMNA gene, is an essential nuclear envelope component in most differentiated cells. Mutations in LMNA have been linked to premature aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS). HGPS is caused by progerin, an aberrant form of lamin A that leads to premature death, typically from the complications of atherosclerotic disease. A key characteristic of HGPS is a severe loss of vascular smooth muscle cells (VSMCs) in the arteries. Various mouse models of HGPS have been created, but few of them feature VSMC depletion and none develops atherosclerosis, the death-causing symptom of the disease in humans. We recently generated a mouse model that recapitulates most features of HGPS, including VSMC loss and accelerated atherosclerosis. Furthermore, by generating cell-type-specific HGPS mouse models, we have demonstrated a central role of VSMC loss in progerin-induced atherosclerosis and premature death.
Topics: Animals; Atherosclerosis; Humans; Lamin Type A; Muscle, Smooth, Vascular; Progeria
PubMed: 30900948
DOI: 10.1080/19491034.2019.1589359 -
Genes Jan 2022Alternative splicing (AS) is a biological operation that enables a messenger RNA to encode protein variants (isoforms) that give one gene several functions or... (Review)
Review
Alternative splicing (AS) is a biological operation that enables a messenger RNA to encode protein variants (isoforms) that give one gene several functions or properties. This process provides one of the major sources of use for understanding the proteomic diversity of multicellular organisms. In combination with post-translational modifications, it contributes to generating a variety of protein-protein interactions (PPIs) that are essential to cellular homeostasis or proteostasis. However, cells exposed to many kinds of stresses (aging, genetic changes, carcinogens, etc.) sometimes derive cancer or disease onset from aberrant PPIs caused by DNA mutations. In this review, we summarize how splicing variants may form a neomorphic protein complex and cause diseases such as Hutchinson-Gilford progeria syndrome (HGPS) and small cell lung cancer (SCLC), and we discuss how protein-protein interfaces obtained from the variants may represent efficient therapeutic target sites to treat HGPS and SCLC.
Topics: Drug Delivery Systems; Humans; Lamin Type A; Lung Neoplasms; Progeria; Proteomics; Small Cell Lung Carcinoma
PubMed: 35205210
DOI: 10.3390/genes13020165 -
Kathmandu University Medical Journal... 2012Our life span is genetically programmed and it is possible that a defect in produced proteins encoded by the longevity gene is a cause of aging. Progeria which is a... (Review)
Review
Our life span is genetically programmed and it is possible that a defect in produced proteins encoded by the longevity gene is a cause of aging. Progeria which is a rare, fatal genetic condition which affects between one in four million and one in eight million children of both sexes equally and characterized by premature and accelerated aging. The appearance and physiology of these children resembles to elderly people but they typically have life span to their mid teens. It is also known as the Hutchinson-Gilford syndrome, which was initially reported by Johnathan Hutchinson in 1886 and further described by Hastings Gilford in 1904. It is an autosomal recessive disorder, which means an individual has inherited a mutated gene from both parents. It is added to the expanding catalogue of laminopathies, diseases caused by mutations affecting nuclear lamina proteins known as lamin A (LMNA). In oral manifestation primary finding is micrognathia with delayed tooth eruption and incomplete formation of root of permanent tooth. Presently there are no known cures for this abnormality.
Topics: Humans; Lamins; Micrognathism; Progeria; Tooth Eruption
PubMed: 22971867
DOI: 10.3126/kumj.v10i1.6919 -
Basic & Clinical Pharmacology &... Oct 2022Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature ageing and early death at a mean age of 14.7 years. At the molecular... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature ageing and early death at a mean age of 14.7 years. At the molecular level, HGPS is caused by a de novo heterozygous mutation in LMNA, the gene encoding A-type lamins (mainly lamin A and C) and nuclear proteins, which have important cellular functions related to structure of the nuclear envelope. The LMNA mutation leads to the synthesis of a truncated prelamin A protein (called progerin), which cannot undergo normal processing to mature lamin A. In normal cells, prelamin A processing involves four posttranslational processing steps catalysed by four different enzymes. In HGPS cells, progerin accumulates as a farnesylated and methylated intermediate in the nuclear envelope where it is toxic and causes nuclear shape abnormalities and senescence. Numerous efforts have been made to target and reduce the toxicity of progerin, eliminate its synthesis and enhance its degradation, but as of today, only the use of farnesyltransferase inhibitors is approved for clinical use in HGPS patients. Here, we review the main current strategies that are being evaluated for treating HGPS, and we focus on efforts to target the posttranslational processing of progerin.
Topics: Adolescent; Farnesyltranstransferase; Humans; Lamin Type A; Nuclear Proteins; Progeria; Protein Processing, Post-Translational
PubMed: 35790078
DOI: 10.1111/bcpt.13770 -
Circulation Jun 2023
Topics: Humans; Progeria; Cellular Senescence; Heart Diseases; Heart; Disease Progression; Lamin Type A
PubMed: 37276251
DOI: 10.1161/CIRCULATIONAHA.123.064765 -
American Journal of Medical Genetics.... Dec 2006Hutchinson-Gilford progeria syndrome (HGPS) is a rare but well known entity characterized by extreme short stature, low body weight, early loss of hair, lipodystrophy,... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is a rare but well known entity characterized by extreme short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early demise. Cognitive development is normal. Data on 10 of our own cases and 132 cases from literature are presented. The incidence in the last century in the Netherlands was 1:4,000,000. Sex ratio was 1.2:1. Main first symptoms were failure to thrive (55%), hair loss (40%), skin problems (28%), and lipodystrophy (20%). Mean age at diagnosis was 2.9 years. Growth in weight was more disturbed than growth in height, and growth delay started already prenatally. Mean height > 13 years was 109.0 cm, mean weight was 14.5 kg. Osteolysis was wide-spread but not expressed, except in the viscerocranium, and remained limited to membranous formed bone. Lipodystrophy is generalized, only intra-abdominal fat depositions remain present. Cardiovascular problems are extremely variable, both in age of onset and nature. Stroke and coronary dysfunctioning are most frequent. Pathologic findings in coronaries and aorta resemble sometimes the findings in elderly persons, but can also be much more limited. Loss of smooth muscle cells seems the most important finding. Mean age of demise was 12.6 years. Patients can be subdivided in patients with classical HGPS, which follows an autosomal dominant pattern of inheritance, (almost) all cases representing spontaneous mutations, and in non-classical progeria, in whom growth can be less retarded, scalp hair remains present for a longer time, lipodystrophy is more slowly progressive, osteolysis is more expressed except in the face, and survival well into adulthood is not uncommon. Pattern of inheritance of non-classical progeria is most probably autosomal recessive. The cause of HGPS is an abnormally formed Lamin A, either directly by a mutated LMNA gene, or through abnormal posttranslational processing (ZMPSTE24 gene mutations). Of 34 LMNA mutations found in progeria patients, there were 26 classical p.G608G mutations (76%). Pathogenesis is most likely to follow several different pathways. Potential therapeutic strategies are developed along these lines and include RNA interference techniques and inhibition of the dominant-negative influence of abnormally formed Lamin A on polymerization with normally formed Lamin A.
Topics: Abnormalities, Multiple; Cardiovascular Diseases; Child; Female; Humans; Infant; Lamin Type A; Male; Models, Genetic; Mutation; Osteolysis; Phenotype; Progeria
PubMed: 16838330
DOI: 10.1002/ajmg.a.31346