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

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.

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Towards a Drosophila model of Hutchinson–Gilford progeria syndrome

Biochemical Society Transactions ◽

10.1042/bst0361389 ◽

2008 ◽

Vol 36 (6) ◽

pp. 1389-1392 ◽

Cited By ~ 6

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.

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A ceRNA analysis on LMNA gene focusing on the Hutchinson-Gilford progeria syndrome

Journal of Clinical Bioinformatics ◽

10.1186/2043-9113-3-2 ◽

2013 ◽

Vol 3 (1) ◽

pp. 2 ◽

Cited By ~ 11

Author(s):

Walter Arancio ◽

Carla Giordano ◽

Giuseppe Pizzolanti

Keyword(s):

Lmna Gene ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

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A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence

Science Translational Medicine ◽

10.1126/scitranslmed.abd2655 ◽

2021 ◽

Vol 13 (575) ◽

pp. eabd2655

Author(s):

Wei Wang ◽

Yuxuan Zheng ◽

Shuhui Sun ◽

Wei Li ◽

Moshi Song ◽

...

Keyword(s):

Cellular Senescence ◽

Werner Syndrome ◽

Embryonic Stem ◽

Accelerated Aging ◽

Premature Aging ◽

Mesenchymal Precursor Cells ◽

Genome Wide ◽

A Genome ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9–based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models. Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24−/− mice that exhibit a premature aging phenotype. CRISPR-Cas9–based genetic screening is a robust method for systematically uncovering senescence genes such as KAT7, which may represent a therapeutic target for developing aging interventions.

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

World Journal for Pediatric and Congenital Heart Surgery ◽

10.1177/2150135118803596 ◽

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.

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

Biochemical Society Transactions ◽

10.1042/bst0380281 ◽

2010 ◽

Vol 38 (1) ◽

pp. 281-286 ◽

Cited By ~ 7

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.

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Hutchinson-Gilford Progeria Syndrome: A Rare Genetic Disorder

Case Reports in Dentistry ◽

10.1155/2013/631378 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4

Author(s):

Rajat G. Panigrahi ◽

Antarmayee Panigrahi ◽

Poornima Vijayakumar ◽

Priyadarshini Choudhury ◽

Sanat K. Bhuyan ◽

...

Keyword(s):

Genetic Disorder ◽

Premature Aging ◽

Pectus Carinatum ◽

Genetic Syndrome ◽

Live Births ◽

Follow Up Study ◽

First Case ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare pediatric genetic syndrome with incidence of one per eight million live births. The disorder is characterised by premature aging, generally leading to death at approximately 13.4 years of age. This is a follow-up study of a 9-year-old male with clinical and radiographic features highly suggestive of HGPS and presented here with description of differential diagnosis and dental consideration. This is the first case report of HGPS which showed pectus carinatum structure of chest.

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Neuropeptide Y Enhances Progerin Clearance and Ameliorates the Senescent Phenotype of Human Hutchinson-Gilford Progeria Syndrome Cells

The Journals of Gerontology Series A ◽

10.1093/gerona/glz280 ◽

2020 ◽

Vol 75 (6) ◽

pp. 1073-1078 ◽

Cited By ~ 3

Author(s):

Célia A Aveleira ◽

Marisa Ferreira-Marques ◽

Luísa Cortes ◽

Jorge Valero ◽

Dina Pereira ◽

...

Keyword(s):

Neuropeptide Y ◽

Caloric Restriction ◽

Cellular Senescence ◽

Dermal Fibroblasts ◽

Cellular Aging ◽

Premature Aging ◽

Whole Body ◽

Lamin A ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Abstract Hutchinson-Gilford progeria syndrome (HGPS, or classical progeria) is a rare genetic disorder, characterized by premature aging, and caused by a de novo point mutation (C608G) within the lamin A/C gene (LMNA), producing an abnormal lamin A protein, termed progerin. Accumulation of progerin causes nuclear abnormalities and cell cycle arrest ultimately leading to cellular senescence. Autophagy impairment is a hallmark of cellular aging, and the rescue of this proteostasis mechanism delays aging progression in HGPS cells. We have previously shown that the endogenous Neuropeptide Y (NPY) increases autophagy in hypothalamus, a brain area already identified as a central regulator of whole-body aging. We also showed that NPY mediates caloric restriction-induced autophagy. These results are in accordance with other studies suggesting that NPY may act as a caloric restriction mimetic and plays a role as a lifespan and aging regulator. The aim of the present study was, therefore, to investigate if NPY could delay HGPS premature aging phenotype. Herein, we report that NPY increases autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from HGPS patients. NPY also rescues nuclear morphology and decreases the number of dysmorphic nuclei, a hallmark of HGPS cells. In addition, NPY decreases other hallmarks of aging as DNA damage and cellular senescence. Altogether, these results show that NPY rescues several hallmarks of cellular aging in HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS.

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Metabolomic profiling suggests systemic signatures of premature aging induced by Hutchinson–Gilford progeria syndrome

Metabolomics ◽

10.1007/s11306-019-1558-6 ◽

2019 ◽

Vol 15 (7) ◽

Cited By ~ 1

Author(s):

Gustavo Monnerat ◽

Geisa Paulino Caprini Evaristo ◽

Joseph Albert Medeiros Evaristo ◽

Caleb Guedes Miranda dos Santos ◽

Gabriel Carneiro ◽

...

Keyword(s):

Premature Aging ◽

Metabolomic Profiling ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

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Hutchinson Gilford Progeria Syndrome with Ocular Manifestation

10.37191/mapsci-joo-1-009 ◽

2021 ◽

Author(s):

Meenakshi Wadhwani

Keyword(s):

Rare Case ◽

Autosomal Dominant ◽

Case Series ◽

Ocular Manifestation ◽

Lmna Gene ◽

Dominant Mutation ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Hutchinson Gilford progeria Syndrome (HPGS) was first described by Jonathan Hutchinson Gilford in 1897 [1]. It is characterized by characteristic facies also described as plucked bird appearance. These are reported to occur due to denovo autosomal dominant mutation in Laminin A(LMNA) gene present on 1q21.1-1q 21.3 and are rarely inherited [2]. This is to report a rare case series of two children presenting with Hutchinson Gilford progeria with ocular manifestation.

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