836 results match your criteria Hutchinson-Gilford Progeria


Mutations Involved in Premature-Ageing Syndromes.

Authors:
Fabio Coppedè

Appl Clin Genet 2021 2;14:279-295. Epub 2021 Jun 2.

Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy.

Premature-ageing syndromes are a heterogeneous group of rare genetic disorders resembling features of accelerated ageing and resulting from mutations in genes coding for proteins required for nuclear lamina architecture, DNA repair and maintenance of genome stability, mitochondrial function and other cellular processes. Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best-characterized progeroid syndromes referred to as childhood- and adulthood-progeria, respectively. This article provides an updated overview of the mutations leading to HGPS, WS, and to the spectrum of premature-ageing laminopathies ranging in severity from congenital restrictive dermopathy (RD) to adult-onset atypical WS, including RD-like laminopathies, typical and atypical HGPS, more and less severe forms of mandibuloacral dysplasia (MAD), Néstor-Guillermo progeria syndrome (NGPS), atypical WS, and atypical progeroid syndromes resembling features of HGPS and/or MAD but resulting from impaired DNA repair or mitochondrial functions, including mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome and mandibuloacral dysplasia associated to (MADaM). Read More

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Systemic transplantation of adult multipotent stem cells prevents articular cartilage degeneration in a mouse model of accelerated ageing.

Immun Ageing 2021 Jun 7;18(1):27. Epub 2021 Jun 7.

Shirley Ryan Abilitylab (Formerly the Rehabilitation Institute of Chicago), 355 E. Erie St, IL, 60611, Chicago, USA.

Background: Osteoarthritis (OA) is one of the most prevalent joint diseases of advanced age and is a leading cause of disability worldwide. Ageing is a major risk factor for the articular cartilage (AC) degeneration that leads to OA, and the age-related decline in regenerative capacity accelerates OA progression. Here we demonstrate that systemic transplantation of a unique population of adult multipotent muscle-derived stem/progenitor cells (MDSPCs), isolated from young wild-type mice, into Zmpste24 mice (a model of Hutchinson-Gilford progeria syndrome, a condition marked by accelerated ageing), prevents ageing-related homeostatic decline of AC. Read More

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Mechanisms of angiogenic incompetence in Hutchinson-Gilford progeria via downregulation of endothelial NOS.

Aging Cell 2021 Jun 4:e13388. Epub 2021 Jun 4.

Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder with features of accelerated aging. The majority of HGPS cases are caused by a de novo point mutation in the LMNA gene (c.1824C>T; p. Read More

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Modeling transcriptomic age using knowledge-primed artificial neural networks.

NPJ Aging Mech Dis 2021 Jun 1;7(1):15. Epub 2021 Jun 1.

Institute for Bioinformatics, University Medicine Greifswald, Greifswald, Germany.

The development of 'age clocks', machine learning models predicting age from biological data, has been a major milestone in the search for reliable markers of biological age and has since become an invaluable tool in aging research. However, beyond their unquestionable utility, current clocks offer little insight into the molecular biological processes driving aging, and their inner workings often remain non-transparent. Here we propose a new type of age clock, one that couples predictivity with interpretability of the underlying biology, achieved through the incorporation of prior knowledge into the model design. Read More

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Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models.

Cells 2021 May 11;10(5). Epub 2021 May 11.

Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease that recapitulates many symptoms of physiological aging and precipitates death. Patients develop severe vascular alterations, mainly massive vascular smooth muscle cell loss, vessel stiffening, calcification, fibrosis, and generalized atherosclerosis, as well as electrical, structural, and functional anomalies in the heart. As a result, most HGPS patients die of myocardial infarction, heart failure, or stroke typically during the first or second decade of life. Read More

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Decreased vascular smooth muscle contractility in Hutchinson-Gilford Progeria Syndrome linked to defective smooth muscle myosin heavy chain expression.

Sci Rep 2021 May 19;11(1):10625. Epub 2021 May 19.

Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Children with Hutchinson-Gilford Progeria Syndrome (HGPS) suffer from multiple cardiovascular pathologies due to the expression of progerin, a mutant form of the nuclear envelope protein Lamin A. Progerin expression has a dramatic effect on arterial smooth muscle cells (SMCs) and results in decreased viability and increased arterial stiffness. However, very little is known about how progerin affects SMC contractility. Read More

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A Link between Replicative Stress, Lamin Proteins, and Inflammation.

Genes (Basel) 2021 Apr 9;12(4). Epub 2021 Apr 9.

Université de Paris and Université Paris-Saclay, INSERM, iRCM/IBFJ, CEA, UMR Stabilité, Génétique Cellules Souches et Radiations, F-92265 Fontenay-aux-Roses, France.

Double-stranded breaks (DSB), the most toxic DNA lesions, are either a consequence of cellular metabolism, programmed as in during V(D)J recombination, or induced by anti-tumoral therapies or accidental genotoxic exposure. One origin of DSB sources is replicative stress, a major source of genome instability, especially when the integrity of the replication forks is not properly guaranteed. To complete stalled replication, restarting the fork requires complex molecular mechanisms, such as protection, remodeling, and processing. Read More

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[Towards gene therapy for Progeria ?]

Authors:
Bertrand Jordan

Med Sci (Paris) 2021 Apr 28;37(4):413-416. Epub 2021 Apr 28.

UMR 7268 ADÉS, Aix-Marseille, Université /EFS/CNRS ; CoReBio PACA, case 901, Parc scientifique de Luminy, 13288 Marseille Cedex 09, France.

Hutchinson-Gilford Progeria (acute premature aging) is caused by a de novo point mutation in the lamin A gene. Recently, this mutation has been accurately corrected by base editing in patient cell lines and in a mouse model, resulting in nearly complete reversal to a normal phenotype. This success opens the perspective for clinical applications in Progeria and other diseases. Read More

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Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A.

Sci Rep 2021 Apr 27;11(1):9122. Epub 2021 Apr 27.

Department of Molecular Biology, Pusan National University, Busan, Republic of Korea.

Werner syndrome (WRN) is a rare progressive genetic disorder, caused by functional defects in WRN protein and RecQ4L DNA helicase. Acceleration of the aging process is initiated at puberty and the expected life span is approximately the late 50 s. However, a Wrn-deficient mouse model does not show premature aging phenotypes or a short life span, implying that aging processes differ greatly between humans and mice. Read More

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Atypical progeroid syndrome (p.E262K LMNA mutation): a rare cause of short stature and osteoporosis.

Endocrinol Diabetes Metab Case Rep 2021 Apr 14;2021. Epub 2021 Apr 14.

Endocrinology Research CentreMoscow, Russia.

Summary: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy-associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophy and metabolic complications but vary differently depending on a particular mutation and even patients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p. Read More

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Jumping on base editing to repair the diseased cardiovascular system in vivo.

Cardiovasc Res 2021 Mar;117(4):e46-e48

Centre for Cardiovascular Science, Queens Medical Research Institute, 47 Little France Crescent, University of Edinburgh, Edinburgh EH16 4TJ, UK.

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A targeted antisense therapeutic approach for Hutchinson-Gilford progeria syndrome.

Nat Med 2021 03 11;27(3):536-545. Epub 2021 Mar 11.

Molecular Genetics Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder characterized by premature death from myocardial infarction or stroke. It is caused by de novo single-nucleotide mutations in the LMNA gene that activate a cryptic splice donor site, resulting in the production of a toxic form of lamin A, which is termed progerin. Here we present a potential genetic therapeutic strategy that utilizes antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to block pathogenic splicing of mutant transcripts. Read More

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Systematic screening identifies therapeutic antisense oligonucleotides for Hutchinson-Gilford progeria syndrome.

Nat Med 2021 03 11;27(3):526-535. Epub 2021 Mar 11.

National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, invariably fatal childhood premature aging disorder caused by a pre-messenger RNA (mRNA) splicing defect in the LMNA gene. We used combined in vitro screening and in vivo validation to systematically explore the effects of target sequence, backbone chemistry and mechanism of action to identify optimized antisense oligonucleotides (ASOs) for therapeutic use in HGPS. In a library of 198 ASOs, the most potent ASOs targeted the LMNA exon 12 junction and acted via non-RNase H-mediated mechanisms. Read More

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Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase.

Life Sci Alliance 2021 05 9;4(5). Epub 2021 Mar 9.

Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA

Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminA mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, β-aminopropionitrile, improves arterial mechanics and cardiac function. Read More

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Statins as a Therapeutic Approach for the Treatment of Pseudoxanthoma Elasticum Patients: Evaluation of the Spectrum Efficacy of Atorvastatin In Vitro.

Cells 2021 Feb 19;10(2). Epub 2021 Feb 19.

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, Germany.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by mutations in the gene. Our previous studies revealed that PXE might be associated with premature aging. Treatment with statins showed positive effects not only for PXE but also for other diseases associated with premature aging like Hutchinson-Gilford progeria syndrome. Read More

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February 2021

The year's new drugs and biologics 2020.

Drugs Today (Barc) 2021 Feb;57(2):101-177

Clarivate, Barcelona, Spain.

2020 will go down in history as a year marked in every respect by the emergence and astonishingly rapid spread of the first major global viral pandemic in a century. It seems like nearly every event or story of the year was influenced in some way by COVID-19, and in that respect, the year ended on a high note with the authorization for emergency use of the first vaccines to prevent SARS-CoV-2 infection and drugs to treat COVID-19. Despite the pandemic's dominance of the 2020 headlines, productivity was at a record high level across all therapeutic areas, as seen by the number of products in this year's review: approximately 50% more than the previous year. Read More

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February 2021

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

Curr Gene Ther 2021 ;21(3):216-229

Department of Pharmacy, Southeast University, Dhaka, Bangladesh.

Lamin A/C encoded by the LMNA gene is an essential component for maintaining 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 that have been identified. Read More

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January 2021

Declining lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity.

Cell Stem Cell 2021 05 24;28(5):967-977.e8. Epub 2021 Feb 24.

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

Neural stem cells (NSCs) generate neurons throughout life in the hippocampal dentate gyrus. With advancing age, levels of neurogenesis sharply drop, which has been associated with a decline in hippocampal memory function. However, cell-intrinsic mechanisms mediating age-related changes in NSC activity remain largely unknown. Read More

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Paclitaxel mitigates structural alterations and cardiac conduction system defects in a mouse model of Hutchinson-Gilford progeria syndrome.

Cardiovasc Res 2021 Feb 24. Epub 2021 Feb 24.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.

Aims: Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare laminopathy caused by expression of progerin, a lamin A variant, also present at low levels in non-HGPS individuals. HGPS patients age and die prematurely, predominantly from cardiovascular complications. Progerin-induced cardiac repolarization defects have been described previously, although the underlying mechanisms are unknown. Read More

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February 2021

Self-assembly of multi-component mitochondrial nucleoids via phase separation.

EMBO J 2021 Mar 23;40(6):e107165. Epub 2021 Feb 23.

National Cancer Institute, NIH, Bethesda, MD, USA.

Mitochondria contain an autonomous and spatially segregated genome. The organizational unit of their genome is the nucleoid, which consists of mitochondrial DNA (mtDNA) and associated architectural proteins. Here, we show that phase separation is the primary physical mechanism for assembly and size control of the mitochondrial nucleoid (mt-nucleoid). Read More

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Clinical and genetic features of children with Hutchinson-Gilford progeria syndrome: a case series and a literature review.

J Eur Acad Dermatol Venereol 2021 Jun 3;35(6):e387-e391. Epub 2021 Apr 3.

Department of Dermatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.

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Lonafarnib: First Approval.

Authors:
Sohita Dhillon

Drugs 2021 Feb;81(2):283-289

Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.

Lonafarnib (Zokinvy™) is an orally active farnesyltransferase inhibitor developed by Eiger BioPharmaceuticals under license from Merck & Co. for the treatment of hepatitis D virus (HDV) infections, and progeria and progeroid laminopathies. The drug was originally discovered by Merck & Co as an investigational drug in oncology. Read More

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February 2021

Long-term survival in a patient with Hutchinson-Gilford progeria syndrome and osteosarcoma: A case report.

World J Clin Cases 2021 Feb;9(4):854-863

Department of Orthopaedic Surgery, Kanazawa University, Kanazawa 9208641, Japan.

Background: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease characterized by the rapid appearance of aging with an onset in childhood. Serious cardiovascular complications can be life-threatening events for affected patients and the cause of early death. Herein we report a HGPS patient with osteosarcoma hat was successfully managed and is alive 13 years after the diagnosis. Read More

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February 2021

A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells.

Elife 2021 Feb 2;10. Epub 2021 Feb 2.

Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.

A farnesylated and methylated form of prelamin A called progerin causes Hutchinson-Gilford progeria syndrome (HGPS). Inhibiting progerin methylation by inactivating the isoprenylcysteine carboxylmethyltransferase (ICMT) gene stimulates proliferation of HGPS cells and improves survival of -deficient mice. However, we don't know whether inactivation improves phenotypes in an authentic HGPS mouse model. Read More

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February 2021

Farnesyltransferase inhibition in HGPS.

Authors:
Tom Misteli

Cell 2021 Jan;184(2):293

National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address:

The ultra-rare, pediatric premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS) is caused by mutation of LMNA, encoding the nuclear architectural protein lamin A. Patients develop atherosclerosis and typically die of heart failure in their teens. FDA-approved Zokinvy prevents farnesylation of lamin A, reduces vascular stiffness, and extends survival in HGPS patients. Read More

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January 2021

Expansion microscopy at the nanoscale: The nuclear pore complex as a fiducial landmark.

Methods Cell Biol 2021 28;161:275-295. Epub 2020 Nov 28.

Nanoscopy and [email protected], CHT, Istituto Italiano di Tecnologia, Genova, Italy; DIFILAB, Dipartimento di Fisica, Universita` degli Studi di Genova, Genova, Italy.

Expansion microscopy (ExM) is a magnification method that allows achieving super-resolved images using a conventional light microscope. In ExM, biomolecules, fluorescent proteins, and dyes are functionalized with specific handles to link a dense polyelectrolyte hydrogel, which can achieve an isotropic expansion of 4.5-fold in water. Read More

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November 2020

Nuclear Pore Complexes Cluster in Dysmorphic Nuclei of Normal and Progeria Cells during Replicative Senescence.

Cells 2021 01 14;10(1). Epub 2021 Jan 14.

Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Technical University of Munich (TUM), 85748 Garching, Germany.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease caused by a mutation in . A G608G mutation in exon 11 of is responsible for most HGPS cases, generating a truncated protein called "progerin". Progerin is permanently farnesylated and accumulates in HGPS cells, causing multiple cellular defects such as nuclear dysmorphism, a thickened lamina, loss of heterochromatin, premature senescence, and clustering of Nuclear Pore Complexes (NPC). Read More

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January 2021

A 13-Year-Old Boy from Thailand with Hutchinson-Gilford Progeria Syndrome with Coronary Artery and Aortic Calcification and Non-ST-Segment Elevation Myocardial Infarction (NSTEMI).

Am J Case Rep 2021 Jan 8;22:e928969. Epub 2021 Jan 8.

Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang-Mai, Thailand.

BACKGROUND Hutchinson-Gilford progeria syndrome (HGPS), also known as progeria, is due to a mutation in the LMNA gene, resulting in a life expectancy of no more than 13 years, and a high mortality rate due to cardiovascular disease. We report the case of a 13-year-old boy from Thailand with Hutchinson-Gilford progeria syndrome with coronary artery and aortic calcification and non-ST-segment elevation myocardial infarction (NSTEMI). CASE REPORT A 13-year-old Thai boy was diagnosed with progeria. Read More

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January 2021