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European Journal of Human Genetics :... Aug 2016We review six previous reports between 2000 and 2014 of seven unrelated patients with mutations in the FBN1 gene affecting function. All mutations occurred in exon 64 of... (Review)
Review
We review six previous reports between 2000 and 2014 of seven unrelated patients with mutations in the FBN1 gene affecting function. All mutations occurred in exon 64 of the FBN1 gene. A distinctive phenotype consisting of partial manifestations of Marfan syndrome, a progeroid facial appearance, and clinical features of lipodystrophy was present in all individuals. We suggest that this previously unknown genotype/phenotype relationship constitutes a new fibrillinopathy for which the name marfanoid-progeroid-lipodystrophy syndrome would be appropriate.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Fibrillin-1; Genetic Pleiotropy; Humans; Lipodystrophy; Male; Marfan Syndrome; Progeria
PubMed: 26860060
DOI: 10.1038/ejhg.2016.6 -
The Journal of Biological Chemistry Dec 2006Hutchinson-Gilford progeria syndrome (HGPS) is caused by a LMNA mutation that leads to the synthesis of a mutant prelamin A that is farnesylated but cannot be further... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is caused by a LMNA mutation that leads to the synthesis of a mutant prelamin A that is farnesylated but cannot be further processed to mature lamin A. A more severe progeroid disorder, restrictive dermopathy (RD), is caused by the loss of the prelamin A-processing enzyme, ZMPSTE24. The absence of ZMPSTE24 prevents the endoproteolytic processing of farnesyl-prelamin A to mature lamin A and leads to the accumulation of farnesyl-prelamin A. In both HGPS and RD, the farnesyl-prelamin A is targeted to the nuclear envelope, where it interferes with the integrity of the nuclear envelope and causes misshapen cell nuclei. Recent studies have shown that the frequency of misshapen nuclei can be reduced by treating cells with a farnesyltransferase inhibitor (FTI). Also, administering an FTI to mouse models of HGPS and RD ameliorates the phenotypes of progeria. These studies have prompted interest in testing the efficacy of FTIs in children with HGPS.
Topics: Animals; Humans; Lamin Type A; Nuclear Proteins; Progeria; Protein Precursors; Protein Prenylation; Syndrome
PubMed: 17090536
DOI: 10.1074/jbc.R600033200 -
Disease Models & Mechanisms Jul 2016Ageing is a process that inevitably affects most living organisms and involves the accumulation of macromolecular damage, genomic instability and loss of... (Review)
Review
Ageing is a process that inevitably affects most living organisms and involves the accumulation of macromolecular damage, genomic instability and loss of heterochromatin. Together, these alterations lead to a decline in stem cell function and to a reduced capability to regenerate tissue. In recent years, several genetic pathways and biochemical mechanisms that contribute to physiological ageing have been described, but further research is needed to better characterize this complex biological process. Because premature ageing (progeroid) syndromes, including progeria, mimic many of the characteristics of human ageing, research into these conditions has proven to be very useful not only to identify the underlying causal mechanisms and identify treatments for these pathologies, but also for the study of physiological ageing. In this Review, we summarize the main cellular and animal models used in progeria research, with an emphasis on patient-derived induced pluripotent stem cell models, and define a series of molecular and cellular hallmarks that characterize progeroid syndromes and parallel physiological ageing. Finally, we describe the therapeutic strategies being investigated for the treatment of progeroid syndromes, and their main limitations.
Topics: Animals; Cellular Reprogramming; Disease Models, Animal; Humans; Mice; Models, Biological; Progeria; Rejuvenation; Syndrome
PubMed: 27482812
DOI: 10.1242/dmm.024711 -
Aging Cell Aug 2018Hereditary and sporadic laminopathies are caused by mutations in genes encoding lamins, their partners, or the metalloprotease ZMPSTE24/FACE1. Depending on the clinical... (Review)
Review
Hereditary and sporadic laminopathies are caused by mutations in genes encoding lamins, their partners, or the metalloprotease ZMPSTE24/FACE1. Depending on the clinical phenotype, they are classified as tissue-specific or systemic diseases. The latter mostly manifest with several accelerated aging features, as in Hutchinson-Gilford progeria syndrome (HGPS) and other progeroid syndromes. MicroRNAs are small noncoding RNAs described as powerful regulators of gene expression, mainly by degrading target mRNAs or by inhibiting their translation. In recent years, the role of these small RNAs has become an object of study in laminopathies using in vitro or in vivo murine models as well as cells/tissues of patients. To date, few miRNAs have been reported to exert protective effects in laminopathies, including miR-9, which prevents progerin accumulation in HGPS neurons. The recent literature has described the potential implication of several other miRNAs in the pathophysiology of laminopathies, mostly by exerting deleterious effects. This review provides an overview of the current knowledge of the functional relevance and molecular insights of miRNAs in laminopathies. Furthermore, we discuss how these discoveries could help to better understand these diseases at the molecular level and could pave the way toward identifying new potential therapeutic targets and strategies based on miRNA modulation.
Topics: Aging, Premature; Animals; Humans; Lamins; MicroRNAs; Progeria
PubMed: 29696758
DOI: 10.1111/acel.12766 -
Indian Journal of Dermatology,... 2010Progeria is a rare genetic disorder characterized by premature aging, involving the skin, bones, heart, and blood vessels. We report a 4-year-old boy who presented with...
Progeria is a rare genetic disorder characterized by premature aging, involving the skin, bones, heart, and blood vessels. We report a 4-year-old boy who presented with clinical manifestations of progeria. He had characteristic facies, prominent eyes, scalp and leg veins, senile look, loss of scalp hair, eyebrows and eyelashes, stunted growth, and sclerodermatous changes. The present case is reported due to its rarity.
Topics: Alopecia; Child, Preschool; Humans; Male; Pigmentation Disorders; Progeria; Scleroderma, Localized
PubMed: 20827016
DOI: 10.4103/0378-6323.69094 -
The Lancet. Child & Adolescent Health Apr 2020Hutchinson-Gilford progeria syndrome (termed progeria in this Article) is a rare sporadic genetic disorder. One early clinical manifestation of progeria is abnormal...
BACKGROUND
Hutchinson-Gilford progeria syndrome (termed progeria in this Article) is a rare sporadic genetic disorder. One early clinical manifestation of progeria is abnormal skeletal growth, yet this growth has not been fully characterised. We aimed to characterise the skeletal maturation and long-bone growth patterns of patients with the clinical phenotype of progeria.
METHODS
For this retrospective study, we reviewed skeletal surveys of patients (aged <20 years) with progeria obtained over a 9·5-year period. Most surveys included radiographs of the hands and long bones (humeri, radii, ulnas, tibias, and fibulas). Bone ages of these patients were estimated by the standards of Greulich and Pyle. Following the established methods for studying long-bone growth, the study cohort was separated into two overlapping age groups: longitudinal bone length measurements were made between physes for the childhood group (aged 12 years or younger) and from the upper margins of the proximal to the lower margin of the distal ossified epiphyses for the adolescent group (aged 10 years or older). Bone age estimates and bone length measurements were plotted against the chronological age of patients and compared with reference standards. Statistical analyses were based on mixed models.
FINDINGS
85 patients with progeria and 250 skeletal surveys were included in our study. For both sexes, bone age estimates showed a more advanced skeletal maturation rate throughout all chronological ages than the normal rate of 1 (p<0·0001), with the rate of maturation being 1·09 (SE 0·02) for boys and 1·14 (0·02) for girls. Longitudinal long-bone lengths began to deviate from normal standards by age 1-2 years. Growth curves for these long bones plateaued at about half the normal eventual bone length, and the half-life (the time taken to grow to half the eventual bone length) was also about half the time compared with normal standards.
INTERPRETATION
Our study established growth curves that might serve as reference standards for skeletal maturation and long-bone growth of patients with the clinical phenotype of progeria.
FUNDING
The Progeria Research Foundation, the US National Heart, Lung and Blood Institute, the Dana-Farber Cancer Institute Stop&Shop Pediatric Brain Tumor Program, the US National Center for Research Resources, US National Institutes of Health.
Topics: Adolescent; Age Determination by Skeleton; Algorithms; Bone Development; Bone Diseases, Developmental; Case-Control Studies; Child; Child, Preschool; Clinical Trials as Topic; Female; Humans; Infant; Male; Phenotype; Progeria; Radiography; Retrospective Studies; Surveys and Questionnaires; Young Adult
PubMed: 32119840
DOI: 10.1016/S2352-4642(20)30023-7 -
Nature Reviews. Molecular Cell Biology Oct 2017Ageing is the predominant risk factor for many common diseases. Human premature ageing diseases are powerful model systems to identify and characterize cellular... (Review)
Review
Ageing is the predominant risk factor for many common diseases. Human premature ageing diseases are powerful model systems to identify and characterize cellular mechanisms that underpin physiological ageing. Their study also leads to a better understanding of the causes, drivers and potential therapeutic strategies of common diseases associated with ageing, including neurological disorders, diabetes, cardiovascular diseases and cancer. Using the rare premature ageing disorder Hutchinson-Gilford progeria syndrome as a paradigm, we discuss here the shared mechanisms between premature ageing and ageing-associated diseases, including defects in genetic, epigenetic and metabolic pathways; mitochondrial and protein homeostasis; cell cycle; and stem cell-regenerative capacity.
Topics: Aging; Aging, Premature; Animals; DNA Repair; Epigenesis, Genetic; Genomic Instability; Humans; Progeria
PubMed: 28792007
DOI: 10.1038/nrm.2017.68 -
Nature Communications Apr 2018Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the...
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements. Recently, we identified Remodelin, a small-molecule agent that leads to amelioration of HGPS cellular defects through inhibition of the enzyme N-acetyltransferase 10 (NAT10). Here, we show the preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances the healthspan in a Lmna HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS.
Topics: Aging, Premature; Animals; DNA Damage; Disease Models, Animal; Female; Genomic Instability; Humans; Hydrazones; Kaplan-Meier Estimate; Lamin Type A; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Terminal Acetyltransferase A; N-Terminal Acetyltransferases; Progeria; Thiazoles
PubMed: 29703891
DOI: 10.1038/s41467-018-03770-3 -
The FEBS Journal May 2021Progeroid laminopathies are characterized by the premature appearance of certain signs of physiological aging in a subset of tissues. They are caused by mutations in... (Review)
Review
Progeroid laminopathies are characterized by the premature appearance of certain signs of physiological aging in a subset of tissues. They are caused by mutations in genes coding for A-type lamins or lamin-binding proteins. Here, we review how different mutations causing progeroid laminopathies alter protein structure or protein-protein interactions and how these impact on mechanisms that protect cell viability and function. One group of progeroid laminopathies, which includes Hutchinson-Gilford progeria syndrome, is characterized by accumulation of unprocessed prelamin A or variants. These are caused by mutations in the A-type lamin gene (LMNA), altering prelamin A itself, or in ZMPSTE24, encoding an endoprotease involved in its processing. The abnormally expressed farnesylated proteins impact on various cellular processes that may contribute to progeroid phenotypes. Other LMNA mutations lead to the production of nonfarnesylated A-type lamin variants with amino acid substitutions in solvent-exposed hot spots located mainly in coil 1B and the immunoglobulin fold domain. Dominant missense mutations might reinforce interactions between lamin domains, thus giving rise to excessively stabilized filament networks. Recessive missense mutations in A-type lamins and barrier-to-autointegration factor (BAF) causing progeroid disorders are found at the interface between these interacting proteins. The amino acid changes decrease the binding affinity of A-type lamins for BAF, which may contribute to lamina disorganization, as well as defective repair of mechanically induced nuclear envelope rupture. Targeting these molecular alterations in A-type lamins and associated proteins identified through structural biology studies could facilitate the design of therapeutic strategies to treat patients with rare but severe progeroid laminopathies.
Topics: Amino Acids; Humans; Intracellular Signaling Peptides and Proteins; Lamin Type A; Laminopathies; Membrane Proteins; Metalloendopeptidases; Mutation, Missense; Nuclear Proteins; Progeria; Protein Conformation
PubMed: 32799420
DOI: 10.1111/febs.15526 -
Science Translational Medicine Feb 2013A clinical trial of a protein farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here,... (Review)
Review
A clinical trial of a protein farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here, we discuss the mutation that causes HGPS, the rationale for inhibiting protein farnesyltransferase, the potential limitations of this therapeutic approach, and new potential strategies for treating the disease.
Topics: Animals; Cell Nucleus Shape; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Lamins; Progeria; Protein Prenylation
PubMed: 23390246
DOI: 10.1126/scitranslmed.3005229