scholarly journals Paradoxical Aortic Stiffening and Subsequent Cardiac Dysfunction in Hutchinson-Gilford Progeria Syndrome

2019 ◽  
Author(s):  
S-I. Murtada ◽  
Y. Kawamura ◽  
A.W. Caulk ◽  
H. Amadzadeh ◽  
N. Mikush ◽  
...  
Keyword(s):  
Late Stage ◽  
Vascular Function ◽  
Systolic Function ◽  
Computational Modelling ◽  
Early Death ◽  
Therapeutic Window ◽  
Lamin A ◽  
Material Stiffness ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

SUMMARYHutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently believed to stem primarily from heart failure secondary to central arterial stiffening. We analyze novel longitudinal cardiovascular data from a mouse model of HGPS (LmnaG609G/G609G) using allometric scaling and advanced computational modelling and show that a late-stage increase in pulse wave velocity, with associated diastolic dysfunction but preserved systolic function, emerges with a loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the entire aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, vascular function appears to be normal within the low stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last quarter of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.DisclosuresD.T.B is an equity holder in, and receives research and consulting support from, Inozyme Pharma, Inc. for therapeutics for ENPP1 deficiency. None of the other authors declare any conflict, financial or otherwise.

scholarly journals Paradoxical aortic stiffening and subsequent cardiac dysfunction in Hutchinson–Gilford progeria syndrome

2020 ◽  
Vol 17 (166) ◽  
pp. 20200066
Author(s):  
S.-I. Murtada ◽  
Y. Kawamura ◽  
A. W. Caulk ◽  
H. Ahmadzadeh ◽  
N. Mikush ◽  
...  
Keyword(s):  
Late Stage ◽  
Vascular Function ◽  
Systolic Function ◽  
Computational Modelling ◽  
Early Death ◽  
Therapeutic Window ◽  
Lamin A ◽  
Material Stiffness ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently thought to stem primarily from cardiovascular events. We analyse novel longitudinal cardiovascular data from a mouse model of HGPS ( Lmna G609G/G609G ) using allometric scaling, biomechanical phenotyping, and advanced computational modelling and show that late-stage diastolic dysfunction, with preserved systolic function, emerges with an increase in the pulse wave velocity and an associated loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and a marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, the vascular function appears to arise normally from the low-stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last third of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.

scholarly journals High-Throughput Screen Detects Calcium Signaling Dysfunction in Hutchinson-Gilford Progeria Syndrome

2021 ◽  
Vol 22 (14) ◽  
pp. 7327
Author(s):  
Juan A. Fafián-Labora ◽  
Miriam Morente-López ◽  
Fco. Javier de Toro ◽  
María C. Arufe
Keyword(s):  
Calcium Signaling ◽  
Rare Disease ◽  
Cell Lines ◽  
Healthy Aging ◽  
Accelerated Aging ◽  
Cytosolic Calcium ◽  
Calcium Handling ◽  
Therapeutic Window ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a deadly childhood disorder, which is considered a very rare disease. It is caused by an autosomal dominant mutation on the LMNA gene, and it is characterized by accelerated aging. Human cell lines from HGPS patients and healthy parental controls were studied in parallel using next-generation sequencing (NGS) to unravel new non-previously altered molecular pathways. Nine hundred and eleven transcripts were differentially expressed when comparing healthy versus HGPS cell lines from a total of 21,872 transcripts; ITPR1, ITPR3, CACNA2D1, and CAMK2N1 stood out among them due to their links with calcium signaling, and these were validated by Western blot analysis. It was observed that the basal concentration of intracellular Ca2+ was statistically higher in HGPS cell lines compared to healthy ones. The relationship between genes involved in Ca2+ signaling and mitochondria-associated membranes (MAM) was demonstrated through cytosolic calcium handling by means of an automated fluorescent plate reading system (FlexStation 3, Molecular Devices), and apoptosis and mitochondrial ROS production were examined by means of flow cytometry analysis. Altogether, our data suggest that the Ca2+ signaling pathway is altered in HGPS at least in part due to the overproduction of reactive oxygen species (ROS). Our results unravel a new therapeutic window for the treatment of this rare disease and open new strategies to study pathologies involving both accelerated and healthy aging.

Towards a Drosophila model of Hutchinson–Gilford progeria syndrome

2008 ◽  
Vol 36 (6) ◽  
pp. 1389-1392 ◽  
Author(s):  
Gemma S. Beard ◽  
Joanna M. Bridger ◽  
Ian R. Kill ◽  
David R.P. Tree
Keyword(s):  
Drosophila Melanogaster ◽  
Premature Aging ◽  
Lamin A ◽  
Wild Type ◽  
Drosophila Model ◽  
Numerous Cell ◽  
Cellular Abnormalities ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Adult Drosophila

The laminopathy Hutchinson–Gilford progeria syndrome (HGPS) is caused by the mutant lamin A protein progerin and leads to premature aging of affected children. Despite numerous cell biological and biochemical insights into the basis for the cellular abnormalities seen in HGPS, the mechanism linking progerin to the organismal phenotype is not fully understood. To begin to address the mechanism behind HGPS using Drosophila melanogaster, we have ectopically expressed progerin and lamin A. We found that ectopic progerin and lamin A phenocopy several effects of laminopathies in developing and adult Drosophila, but that progerin causes a stronger phenotype than wild-type lamin A.

scholarly journals iPSC-Derived Endothelial Cells Affect Vascular Function in a Tissue-Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome

2020 ◽  
Vol 14 (2) ◽  
pp. 325-337 ◽  
Author(s):  
Leigh Atchison ◽  
Nadia O. Abutaleb ◽  
Elizabeth Snyder-Mounts ◽  
Yantenew Gete ◽  
Alim Ladha ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessel ◽  
Vascular Function ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

scholarly journals A Very Rare Case of Coronary Artery Bypass Grafting in a Progeria Child

2019 ◽  
Vol 11 (4) ◽  
pp. NP244-NP246
Author(s):  
Rui Pedro Soares Cerejo ◽  
Rui A. N. Rodrigues ◽  
José D. Martins ◽  
Carolina G. E. C. Torres ◽  
Lídia M. Sousa ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Genetic Disorder ◽  
Artery Bypass ◽  
Early Death ◽  
Premature Aging ◽  
Artery Disease ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Vessel Coronary Artery

Hutchinson-Gilford progeria syndrome is a rare genetic disorder, characterized by progressive premature aging and early death in the first or second decade of life, usually secondary to cardiovascular events (myocardial infarction and stroke). We report a case of a 14-year-old boy with progeria syndrome and cardiac arrest due to myocardial infarction, who was submitted to an immediate coronary angiography which revealed left main stem and three-vessel coronary artery disease. A prompt double bypass coronary artery grafting surgery was performed, and, despite successful coronary reperfusion, the patient remained in coma and brain death was declared on fourth day after surgery.

Lamin A-linked progerias: is farnesylation the be all and end all?

2010 ◽  
Vol 38 (1) ◽  
pp. 281-286 ◽  
Author(s):  
Dawn T. Smallwood ◽  
Sue Shackleton
Keyword(s):  
Clinical Trials ◽  
Aging Process ◽  
Gene Mutations ◽  
Accelerated Aging ◽  
Membrane Dynamics ◽  
Lamin A ◽  
Farnesyltransferase Inhibitors ◽  
C Terminus ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

HGPS (Hutchinson–Gilford progeria syndrome) is a severe childhood disorder that appears to mimic an accelerated aging process. The disease is most commonly caused by gene mutations that disrupt the normal post-translational processing of lamin A, a structural component of the nuclear envelope. Impaired processing results in aberrant retention of a farnesyl group at the C-terminus of lamin A, leading to altered membrane dynamics. It has been widely proposed that persistence of the farnesyl moiety is the major factor responsible for the disease, prompting clinical trials of farnesyltransferase inhibitors to prevent lamin A farnesylation in children afflicted with HGPS. Although there is evidence implicating farnesylation in causing some of the cellular defects of HGPS, results of several recent studies suggest that aberrant lamin A farnesylation is not the only determinant of the disease. These findings have important implications for the design of treatments for this devastating disease.

scholarly journals A pathway linking oxidative stress and the Ran GTPase system in progeria

2014 ◽  
Vol 25 (8) ◽  
pp. 1202-1215 ◽  
Author(s):  
Sutirtha Datta ◽  
Chelsi J. Snow ◽  
Bryce M. Paschal
Keyword(s):  
Oxidative Stress ◽  
Nuclear Membrane ◽  
Nucleocytoplasmic Transport ◽  
Lamin A ◽  
Mutant Form ◽  
Ran Gtpase ◽  
Nuclear Levels ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
The Relationship

Maintaining the Ran GTPase at a proper concentration in the nucleus is important for nucleocytoplasmic transport. Previously we found that nuclear levels of Ran are reduced in cells from patients with Hutchinson–Gilford progeria syndrome (HGPS), a disease caused by constitutive attachment of a mutant form of lamin A (termed progerin) to the nuclear membrane. Here we explore the relationship between progerin, the Ran GTPase, and oxidative stress. Stable attachment of progerin to the nuclear membrane disrupts the Ran gradient and results in cytoplasmic localization of Ubc9, a Ran-dependent import cargo. Ran and Ubc9 disruption can be induced reversibly with H2O2. CHO cells preadapted to oxidative stress resist the effects of progerin on Ran and Ubc9. Given that HGPS-patient fibroblasts display elevated ROS, these data suggest that progerin inhibits nuclear transport via oxidative stress. A drug that inhibits pre–lamin A cleavage mimics the effects of progerin by disrupting the Ran gradient, but the effects on Ran are observed before a substantial ROS increase. Moreover, reducing the nuclear concentration of Ran is sufficient to induce ROS irrespective of progerin. We speculate that oxidative stress caused by progerin may occur upstream or downstream of Ran, depending on the cell type and physiological setting.

scholarly journals Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

2008 ◽  
Vol 19 (12) ◽  
pp. 5238-5248 ◽  
Author(s):  
Brian A. Kudlow ◽  
Monique N. Stanfel ◽  
Christopher R. Burtner ◽  
Elijah D. Johnston ◽  
Brian K. Kennedy
Keyword(s):  
Human Fibroblasts ◽  
Rapid Onset ◽  
Lamin A ◽  
Premature Senescence ◽  
Inhibition Of Proliferation ◽  
Nuclear Lamins ◽  
Cell Immortalization ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Telomere Structure

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, debilitating disease with early mortality and rapid onset of aging-associated pathologies. It is linked to mutations in LMNA, which encodes A-type nuclear lamins. The most frequent HGPS-associated LMNA mutation results in a protein, termed progerin, with an internal 50 amino acid deletion and, unlike normal A-type lamins, stable farnesylation. The cellular consequences of progerin expression underlying the HGPS phenotype remain poorly understood. Here, we stably expressed lamin A mutants, including progerin, in otherwise identical primary human fibroblasts to compare the effects of different mutants on nuclear morphology and cell proliferation. We find that expression of progerin leads to inhibition of proliferation in a high percentage of cells and slightly premature senescence in the population. Expression of a stably farnesylated mutant of lamin A phenocopied the immediate proliferative defects but did not result in premature senescence. Either p53 inhibition or, more surprisingly, expression of the catalytic subunit of telomerase (hTERT) suppressed the early proliferative defects associated with progerin expression. These findings lead us to propose that progerin may interfere with telomere structure or metabolism in a manner suppressible by increased telomerase levels and possibly link mechanisms leading to progeroid phenotypes to those of cell immortalization.

Sign in / Sign up

Export Citation Format

Share Document