Hutchinson-Gilford Progeria Syndrome: An Overview of the Molecular Mechanism, Pathophysiology and Therapeutic Approach

2021 ◽  
Vol 21 ◽  
Author(s):  
Md. Mominur Rahman ◽  
Kazi Sayma Ferdous ◽  
Muniruddin Ahmed ◽  
Mohammad Touhidul Islam ◽  
Md. Robin Khan ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Nuclear Structure ◽  
Early Stage ◽  
Treatment Options ◽  
Lamin A ◽  
Lmna Gene ◽  
Inherited Disorders ◽  
Appropriate Treatment ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

: Lamin A/C encoded by LMNA gene is an important component for the maintenance of the nuclear structure. Mutation in the lamin A/C leads to a group of inherited disorders is known as laminopathies. In the human body, there are several mutations in the LMNA gene have been identified. It can affect diverse organs or tissues or can be systemic, causing different diseases. In this review, we mainly focused on one of the most severe laminopathies, Hutchinson-Gilford progeria syndrome (HGPS). HGPS is an immensely uncommon, deadly, metameric ill-timed laminopathies caused by the abnormal splicing of the LMNA gene and production of an aberrant protein known as progerin. Here, we also presented the currently available data on the molecular mechanism, pathophysiology, available treatment, and future approaches of this deadly disease. Due to the production of progerin an abnormal protein leads to an abnormality in nuclear structure, defects in DNA repair, shortening of telomere, impairment in gene regulation which ultimately results in aging in the early stage of life. Now some treatment options are available for this disease but a proper understanding of the molecular mechanism of this disease will help to develop a more appropriate treatment which makes it an emerging area of research.

Emerging candidate treatment strategies for Hutchinson-Gilford progeria syndrome

2017 ◽  
Vol 45 (6) ◽  
pp. 1279-1293 ◽  
Author(s):  
Charlotte Strandgren ◽  
Gwladys Revêchon ◽  
Agustín Sola Carvajal ◽  
Maria Eriksson
Keyword(s):  
De Novo ◽  
Disease Incidence ◽  
Treatment Strategies ◽  
Premature Aging ◽  
Lamin A ◽  
Lmna Gene ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS, progeria) is an extremely rare premature aging disorder affecting children, with a disease incidence of ∼1 in 18 million individuals. HGPS is usually caused by a de novo point mutation in exon 11 of the LMNA gene (c.1824C>T, p.G608G), resulting in the increased usage of a cryptic splice site and production of a truncated unprocessed lamin A protein named progerin. Since the genetic cause for HGPS was published in 2003, numerous potential treatment options have rapidly emerged. Strategies to interfere with the post-translational processing of lamin A, to enhance progerin clearance, or directly target the HGPS mutation to reduce the progerin-producing alternative splicing of the LMNA gene have been developed. Here, we give an up-to-date resume of the contributions made by our and other research groups to the growing list of different candidate treatment strategies that have been tested, both in vitro, in vivo in mouse models for HGPS and in clinical trials in HGPS patients.

Nuclear stiffening and chromatin softening with progerin expression leads to an attenuated nuclear response to force

Soft Matter ◽  
2015 ◽  
Vol 11 (32) ◽  
pp. 6412-6418 ◽  
Author(s):  
Elizabeth A. Booth ◽  
Stephen T. Spagnol ◽  
Turi A. Alcoser ◽  
Kris Noel Dahl
Keyword(s):  
Nuclear Structure ◽  
Nuclear Protein ◽  
Premature Aging ◽  
Lamin A ◽  
Mutant Form ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Nuclear Response

Progerin, a mutant form of the nuclear protein lamin A, is associated with the premature aging disorder Hutchinson-Gilford progeria syndrome. Progerin expression leads to a variety of changes in nuclear structure, mechanics and mechano-responsiveness.

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.

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.

scholarly journals New Lmna knock-in mice provide a molecular mechanism for the ‘segmental aging’ in Hutchinson–Gilford progeria syndrome†

2013 ◽  
Vol 23 (6) ◽  
pp. 1506-1515 ◽  
Author(s):  
Hea-Jin Jung ◽  
Yiping Tu ◽  
Shao H. Yang ◽  
Angelica Tatar ◽  
Chika Nobumori ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome
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