Imaging Characteristics of Cerebrovascular Arteriopathy and Stroke in Hutchinson-Gilford Progeria Syndrome

Silvera, V. Michelle; Gordon, L.B.; Orbach, Darren B.; Campbell, Susan; Machan, Jason T.; Ullrich, Nicole J.

doi:10.3174/ajnr.a3341

Cited by 56 publications

(44 citation statements)

References 24 publications

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“…Cardiac manifestations include increased afterload and angina (Ullrich and Gordon 2015). Remarkably, it is estimated that 50% of children have radiographically detectable strokes by the age of eight, and infarcts were common on imaging studies of patients between five and 10 years of age (Silvera, Gordon et al 2013). Most of these strokes are often clinically silent.…”

Section: Pathophysiology Of Hgpsmentioning

confidence: 99%

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

Gonzalo

Kreienkamp

Askjaer

2017

Ageing Research Reviews

229

210

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Products of the LMNA gene, primarily lamin A and C, are key components of the nuclear lamina, a proteinaceous meshwork that underlies the inner nuclear membrane and is essential for proper nuclear architecture. Alterations in lamin A and C that disrupt the integrity of the nuclear lamina affect a whole repertoire of nuclear functions, causing cellular decline. In humans, hundreds of mutations in the LMNA gene have been identified and correlated with over a dozen degenerative disorders, referred to as laminopathies. These diseases include neuropathies, muscular dystrophies, lipodystrophies, and premature aging diseases. This review focuses on one of the most severe laminopathies, Hutchinson-Gilford Progeria Syndrome (HGPS), which is caused by aberrant splicing of the LMNA gene and expression of a mutant product called progerin. Here, we discuss current views about the molecular mechanisms that contribute to the pathophysiology of this devastating disease, as well as the strategies being tested in vitro and in vivo to counteract progerin toxicity. In particular, progerin accumulation elicits nuclear morphological abnormalities, misregulated gene expression, defects in DNA repair, telomere shortening, and genomic instability, all of which limit cellular proliferative capacity. In patients harboring this mutation, a severe premature aging disease develops during childhood. Interestingly, progerin is also produced in senescent cells and cells from old individuals, suggesting that progerin accumulation might be a factor in physiological aging. Deciphering the molecular mechanisms whereby progerin expression leads to HGPS is an emergent area of research, which could bring us closer to understanding the pathology of aging.

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Section: Pathophysiology Of Hgpsmentioning

confidence: 99%

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

Gonzalo

Kreienkamp

Askjaer

2017

Ageing Research Reviews

229

210

View full text Add to dashboard Cite

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“…HGPS patients suffer from early severe cardiovascular diseases which are characterized by progressive atherosclerosis [3], [4], adventitial fibrosis and left ventricular hypertrophy [5]. They typically die from myocardial infarction or ischemic attack at the average age of 13 [6].…”

Section: Introductionmentioning

confidence: 99%

An Upregulation in the Expression of Vanilloid Transient Potential Channels 2 Enhances Hypotonicity-Induced Cytosolic Ca2+ Rise in Human Induced Pluripotent Stem Cell Model of Hutchinson Gillford Progeria

Tjong

et al. 2014

PLoS ONE

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Hutchinson-Gillford Progeria Syndrome (HGPS) is a fatal genetic disorder characterized by premature aging in multiple organs including the skin, musculoskeletal and cardiovascular systems. It is believed that an increased mechanosensitivity of HGPS cells is a causative factor for vascular cell death and vascular diseases in HGPS patients. However, the exact mechanism is unknown. Transient receptor potential (TRP) channels are cationic channels that can act as cellular sensors for mechanical stimuli. The aim of this present study was to examine the expression and functional role of TRP channels in human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from the patients with HGPS. The mRNA and protein expression of TRP channels in HGPS and control (IMR90) iPSC-ECs were examined by semi-quantitative RT-PCRs and immunoblots, respectively. Hypotonicity-induced cytosolic Ca2+ ([Ca2+]i) rise in iPSC-ECs was measured by confocal microscopy. RT-PCRs and immunoblots showed higher expressional levels of TRPV2 in iPSC-ECs from HGPS patients than those from normal individuals. In functional studies, hypotonicity induced a transient [Ca2+]i rise in iPSC-ECs from normal individuals but a sustained [Ca2+]i elevation in iPSC-ECs from HGPS patients. A nonselective TRPV inhibitor, ruthenium red (RuR, 20 µM), and a specific TRPV2 channel inhibitor, tranilast (100 µM), abolished the sustained phase of hypotonicity-induced [Ca2+]i rise in iPSC-ECs from HGPS patients, and also markedly attenuated the transient phase of the [Ca2+]i rise in these cells. Importantly, a short 10 min hypotonicity treatment caused a substantial increase in caspase 8 activity in iPSC-ECs from HGPS patients but not in cells from normal individuals. Tranilast could also inhibit the hypotonicity-induced increase in caspase 8 activity. Taken together, our data suggest that an up-regulation in TRPV2 expression causes a sustained [Ca2+]i elevation in HGPS-iPSC-ECs under hypotonicity, consequently resulting in apoptotic cell death. This mechanism may contribute to the pathogenesis of vascular diseases in HGPS patients.

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“…This has led, for example, to a proposed revision of the clinical diagnostic criteria for WS, to the discovery that cerebral infarctions in HGPS are more frequent than expected, and to a better understanding of cancer incidence in WS, among others 12,38,39…”

Section: Resultsmentioning

confidence: 99%

“…Cerebrovascular arteriopathy and stroke have been recently assessed by means of a neurovascular imaging cohort study of HGPS, a study aimed to identify the neurovascular features, infarct type, topography, and natural history of stroke 12. A total of 25 children with confirmed diagnoses of HGPS were included in the study, which revealed a vasculopathy unique to HGPS, including distinctive intracranial stenoocclusive arterial lesions, basal cistern collateral vessels, and slow compensatory collateral flow over the cerebral convexities.…”

Section: Hutchinson–gilford Progeria Syndromementioning

confidence: 99%

The epidemiology of premature aging and associated comorbidities

Coppedè¹

2013

CIA

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Hutchinson–Gilford Progeria Syndrome and Werner syndrome, also known as childhood- and adulthood-progeria, respectively, represent two of the best characterized human progeroid diseases with clinical features mimicking physiological aging at an early age. The discovery of their genetic basis has led to the identification of several gene mutations leading to a spectrum of progeroid phenotypes ranging from moderate and mild–severe to very aggressive forms. In parallel, the creation of disease registers and databases provided available data for the design of relatively large-scale epidemiological studies, thereby allowing a better understanding of the nature and frequency of the premature aging-associated signs and symptoms. The aim of this article is to review the most recent findings concerning the epidemiology of premature aging disorders, their genetic basis, and the most recent reports on the frequency of associated diseases.

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Imaging Characteristics of Cerebrovascular Arteriopathy and Stroke in Hutchinson-Gilford Progeria Syndrome

Cited by 56 publications

References 24 publications

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

An Upregulation in the Expression of Vanilloid Transient Potential Channels 2 Enhances Hypotonicity-Induced Cytosolic Ca2+ Rise in Human Induced Pluripotent Stem Cell Model of Hutchinson Gillford Progeria

The epidemiology of premature aging and associated comorbidities

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