Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Nestor-Guillermo progeria syndrome. Core disease mechanisms, molecular and...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 18
• Snippets retrieved: 20

Relevant Papers

[1] Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells

• Authors: Dido Carrero, C. Soria-Valles, C. López-Otín
• Year: 2016
• Venue: Disease Models & Mechanisms
• URL: https://www.semanticscholar.org/paper/ec1ed5c2e45d4aeb1fcd088517438dc345058b88
• DOI: 10.1242/dmm.024711
• PMID: 27482812
• PMCID: 4958309
• Citations: 137
• Influential citations: 8
• Summary: A series of molecular and cellular hallmarks that characterize progeroid syndromes and parallel physiological ageing are defined and the therapeutic strategies developed to date are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.649) > characteristics of progeroid syndromes and define the mechanisms underlying their pathogenesis, which could provide ideas for future studies on both physiological and pathological ageing. Finally, we review different therapeutic strategies developed for the treatment of these rare but devastating diseases. > A classification system for human progeroid syndromes All progeroid syndromes are characterized by similar clinical features (Table 1), but their underlying mechanisms can vary depending on the mutated gene and the pathway that is consequently altered. Below, we have classified progeroid syndromes into two general categories based on the molecular pathway involved. The first group includes those syndromes caused by alterations in components of the nuclear envelope, such as Hutchinson-Gilford progeria syndrome (HGPS), Néstor-Guillermo progeria syndrome (NGPS), atypical progeria syndromes (APSs), restrictive dermopathy (RD) and mandibuloacral dysplasia (MAD). The second group consists of progeroid syndromes induced by mutations in genes involved in DNA-repair pathways, such as Werner syndrome (WS), Bloom syndrome (BS), Rothmund-Thomson syndrome (RTS), Cockayne syndrome (CS), xeroderma pigmentosum (XP), trichothiodystrophy (TTD), Fanconi anaemia (FA), Seckel syndrome (SS), ataxia telangiectasia (AT), ataxia telangiectasia-like disorder (ATLD), cerebroretinal microangiopathy with calcifications and cysts (CRMCC), and Nijmegen breakage syndrome (NBN). A subcategory of this group comprises dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson syndrome (HHS), linked to mutations in components of the telomerase complex (see Box 1 for a glossary of terms) that cause telomere attrition.
• Snippet 2 (score: 0.488) > The physiological deterioration that accompanies ageing constitutes a major risk factor for the development of human pathologies, such as cancer, cardiovascular disorders and neurodegenerative diseases . Key molecular hallmarks of the ageing phenotype include telomere attrition, genomic instability, loss of proteostasis, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, stem cell exhaustion, cellular senescence and altered intercellular communication . At the macromolecular level, ageing is characterized by the development of wrinkles, greying and loss of hair, presbyopia, osteoarthritis and osteoporosis, progressive loss of fertility, loss of muscle mass and mobility, decreased cognitive ability, hearing loss, and a higher risk for the development of cancer and heart diseases, among other features (López-Otín et al., 2013). > Progeroid syndromes are a group of very rare genetic disorders that are characterized by clinical features that mimic physiological ageing, such as hair loss, short stature, skin tightness, cardiovascular diseases and osteoporosis. Consequently, they constitute a relevant source of information to understand the molecular mechanisms involved in normal ageing. Progeroid disorders do not show differences in prevalence depending on sex or ethnic origin, and appear at an early age, mainly due to defects in the nuclear envelope and DNA repair mechanisms (Gordon et al., 2014). Affected individuals die at a young age, usually as a consequence of cardiovascular problems and musculoskeletal degeneration. > In this Review, we classify human progeroid syndromes into two main groups according to the mechanisms that underlie the disease. Next, we discuss recent findings in the study of progeroid syndromes, achieved through the use of cellular and animal models. On the basis of these findings, we propose nine candidate hallmarks of premature ageing, and highlight their similarities with those described for physiological ageing. These proposed hallmarks recapitulate the most remarkable characteristics of progeroid syndromes and define the mechanisms underlying their pathogenesis, which could provide ideas for future studies on both physiological and pathological ageing. Finally, we review different therapeutic strategies developed for the treatment of these rare but devastating diseases. > A classification system for human progeroid syndromes All progeroid

[2] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

• Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
• Year: 2026
• Venue: Nucleus
• URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
• DOI: 10.1080/19491034.2025.2611484
• PMID: 41489464
• PMCID: 12773485
• Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
• Evidence snippets:
• Snippet 1 (score: 0.568) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[3] The Molecular and Cellular Basis of Hutchinson–Gilford Progeria Syndrome and Potential Treatments

• Authors: Noelle Batista, Sanket Desai, Alexis M. Perez, Alex L. Finkelstein, Rachel Radigan et al.
• Year: 2023
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/c1a733c670261a8f92c0a0ec4b725c76608136ff
• DOI: 10.3390/genes14030602
• PMID: 36980874
• PMCID: 10048386
• Citations: 26
• Influential citations: 4
• Summary: At a clinical level, HGPS does not fully match normal aging because of the accelerated nature of the phenotypes and its primary effects on connective tissues, but various treatments for the HGPS patients have been developed in recent years with important effects at a cellular level, which translate to symptomatic improvement and increased lifespan.
• Evidence snippets:
• Snippet 1 (score: 0.545) > Normal aging refers to a time-dependent deterioration of cells, tissues, and overall physiological functions accompanied by an increased risk of various pathologies, including cancer, cardiovascular disease, diabetes, and neurodegeneration [1]. Pathological aging, most notably the progeroid syndromes, can rapidly accelerate these risks [1,2]. Attempts to examine their causes have revealed major gaps in our current understanding of how the aging mechanism works. Furthering our knowledge of the underlying molecular and cellular processes of abnormal aging is necessary to gain insight into the development and detection of aging-related diseases, to identify novel therapeutic approaches, and overall to improve human health during aging [1]. > Progeroid syndromes, also referred to as premature aging disorders, encompass a heterogeneous group of rare, highly fatal, and hereditary diseases that appear to recapitulate multiple phenotypes of advanced physiological aging extremely early on in development [3]. One of the earliest reported cases of a progeroid syndrome was first published in 1886 and depicted some of the harsh clinical manifestations of the disease in a three-year-old child [4]. This report described what is now referred to as Hutchinson-Gilford Progeria Syndrome (HGPS). Investigations of the molecular basis of these progeroid diseases have revealed perturbations of critical cellular processes such as DNA replication, DNA repair, and the formation of nuclear membrane architecture [5]. Interestingly, new evidence suggests that the physical properties and connections at the nuclear-cytoskeletal interface directly contribute to numerous cellular functions, including mechanotransduction [6,7]. Mechanotransduction is the process by which cells convert mechanical signals from the extracellular matrix into biochemical signaling pathways transmitted from the cytoskeleton to the nucleus and across the nuclear envelope to the nuclear lamina and chromatin. Notably, this has been shown to result in downstream signaling and altered gene expression [6,7].

[4] Premature aging disorders: A clinical and genetic compendium

• Authors: F. Schnabel, U. Kornak, B. Wollnik
• Year: 2020
• Venue: Clinical Genetics
• URL: https://www.semanticscholar.org/paper/dc397fd4689a750a54dea921c92d502a74300d6c
• DOI: 10.1111/cge.13837
• PMID: 32860237
• Citations: 47
• Influential citations: 2
• Summary: This review provides a detailed overview on characteristic clinical features and underlying molecular genetics of well‐known as well as only recently identified premature aging disorders and also highlights novel findings towards future therapeutic options.
• Evidence snippets:
• Snippet 1 (score: 0.515) > nuclear lamina proteins leading to the disruption of the nuclear envelope and to nuclear blebbing are more related to HGPS, Nestor-Guillermo progeria syndrome, restrictive dermopathy, and mandibuloacral dysplasia. Defects in DNA repair causing genomic instability and increased cancer risk are associated with RecQ helicase-mutant disorders such as Werner syndrome, Bloom syndrome and Rothmund-Thomson syndrome, but play also a role in Ataxia-telangiectasia, Cockayne syndrome, Nijmegen breakage syndrome, Seckel syndrome and xeroderma pigmentosum, among others. > Major effects of telomere attrition are for example known for dyskeratosis congenital and Hoyeraal-Hreidarsson syndrome, 3 although telomere dysfunction has been described in almost all premature aging syndromes associated with genomic instability. Likewise, mitochondrial dysfunction is frequently observed. It is a key characteristic of Fontaine progeroid syndrome and some progeroid cutis laxa syndromes, but also contributes to the pathogenesis of several other progeroid disorders such as HGPS, mandibuloacral dysplasia type B, Cockayne syndrome, ataxia-telangiectasia, and xeroderma pigmentosum. 6 Hereinafter, we give an overview of well-known and brand-new premature aging disorders, their clinical characteristics and their molecular basis. The detailed phenotypes are summarized in Table 1. > We have selected these disorders based on prevalance, awareness level, novel insights, and the authors' interest to present the disease spectrum. The described conditions result from different major molecular mechanisms such as nuclear lamina alterations, genomic instability and mitochondrial dysfunction, but also include additional premature aging phenotypes with an alternative or unknown pathogenesis. Based on these criteria, we performed a systematic search in F I G U R E 1 Hallmarks of aging disorders. This schematic illustration summarizes the nine proposed molecular and cellular mechanisms underlying progeroid diseases (adapted from López-Otín et al. 1 PubMed and OMIM database for premature aging disorders in general and separately for each condition.

[5] Functional relevance of miRNAs in premature ageing.

• Authors: Xurde M. Caravia, David Roiz-Valle, Alba Morán-Álvarez, C. López-Otín
• Year: 2017
• Venue: Mechanisms of ageing and development
• URL: https://www.semanticscholar.org/paper/5705c3943afa7a584cf2dd5cb574dd5285fc1ddc
• DOI: 10.1016/j.mad.2017.05.003
• PMID: 28502819
• Citations: 13
• Summary: The functional relevance of this class of small non-coding RNAs in the regulation of the hallmarks of progeroid syndromes is addressed and the potential strategies for managing progeria based on geromiR modulation are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.502) > Being undoubtedly detrimental, these processes are the main culprits of ageing-associated macromolecular damage. Mitochondrial dysfunction, cellular senescence and deregulated nutrient sensing fall into the second category of compensatory or antagonistic responses that counterbalance the primary hallmarks. These processes have an initial benign effect up to a point when they turn to be deleterious. Finally, the third category involves the integrative hallmarks and includes altered intercellular communication and stem cell exhaustion. These hallmarks are ultimately responsible for the functional decline associated with ageing. More recently, the metabolic pathways which play a role in controlling ageing and longevity have also been defined, along with metabolism-related interventions that proved to extend longevity in several model organisms. Amongst these interventions are regular exercise, dietary restriction and its pharmacological mimetics (resveratrol and spermidine), the limited intake of amino acids, the administration of metformin (an antidiabetic drug) and the inhibition of trophic signal-transduction pathways . > Progeroid syndromes comprise a group of genetic disorders in which patients show ageing phenotypes in their youth (Ramírez et al., 2007). In spite of the many different progeroid diseases described to date, they can be categorized into two main subgroups that are defined by their etiology. Hence, the first type of progeroid syndromes  known as laminopathies  is caused by mutations in nuclear lamina components. This category includes Hutchinson-Gilford (HGPS) and Néstor-Guillermo (NGPS) progeria syndromes, other atypical progeria syndromes (APS), restrictive dermopathy (RD) and mandibuloacral dysplasia (MAD). The second group of progeroid syndromes stems from defects in DNA repair mechanisms. Here we can find Werner syndrome (WS), Bloom syndrome (BS), Rothmund-Thomson syndrome (RTS), Seckel syndrome (SS), Cockayne syndrome (CS), Hoyeraal-Hreidarsson syndrome (HHS), xeroderma pigmentosum (XP), trichothiodystrophy (TTD), Fanconi anemia (FA), ataxia tel

[6] Molecular mechanisms of normal and pathological aging

• Authors: C. López-Otín
• Year: 2015
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/64f51591844c1a49f1822a5a93ed67961466777f
• DOI: 10.1186/1750-1172-10-S2-O1
• PMCID: 4652548
• Summary: It is shown that nuclear envelope defects causative of these complex diseases lead to alterations in stem cell functionality, epigenetic abnormalities, perturbations in cell senescence pathways, metabolic changes and chronic activation of inflammatory responses and the genetic or pharmacological blockade of these altered pathways prevents the development of many age-associated features of these progeroid mice and extends their longevity.
• Evidence snippets:
• Snippet 1 (score: 0.496) > We have recently defined nine molecular and cellular hallmarks that represent common denominators of aging in different organisms. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. On the other hand, parallel studies of our laboratory on accelerated aging syndromes, including Hutchinson-Gilford Progeria Syndrome (HGPS) and Nestor-Guillermo Progeria Syndrome (NGPS), have provided relevant information about these hallmarks of aging. HGPS is caused by a point mutation in the LMNA gene that yields a truncated form of prelamin A called progerin, which is also produced during normal aging. Over the last years, the generation of mouse models of HGPS and other progeroid laminopathies has shed light on the molecular alterations functionally involved in these diseases. Thus, knock-out mice deficient in Zmpste24 metalloproteinase implicated in prelamin A maturation, mosaic mice containing Zmpste24-deficient and Zmpste24-proficient cells, and knock-in mice carrying the human HGPS mutation which causes progerin accumulation, have allowed us to demonstrate that progeroid laminopathies result from the combined action of both cell-autonomous and systemic factors. Accordingly, we have shown that nuclear envelope defects causative of these complex diseases lead to alterations in stem cell functionality, epigenetic abnormalities, perturbations in cell senescence pathways, metabolic changes and chronic activation of inflammatory responses. We have also demonstrated that the genetic or pharmacological blockade of these altered pathways prevents the development of many age-associated features of these progeroid mice and extends their longevity. On this basis, we have developed therapeutic strategies for progeroid laminopathies which are now in clinical trials coordinated by Pr. Nicolas Levy for the treatment of HGPS patients. These findings illustrate the importance of mouse models for designing therapeutic strategies to treat rare and dramatic progeroid syndromes as well as for improving our knowledge of the universal and complex process of human aging.

[7] Néstor-Guillermo Progeria Syndrome: a biochemical insight into Barrier-to-Autointegration Factor 1, alanine 12 threonine mutation

• Authors: N. Paquet, J. Box, Nicholas W. Ashton, Amila Suraweera, L. Croft et al.
• Year: 2014
• Venue: BMC Molecular Biology
• URL: https://www.semanticscholar.org/paper/7bed336d438aa40c7fb3977c4f52a644de6b77f5
• DOI: 10.1186/s12867-014-0027-z
• PMID: 25495845
• PMCID: 4266902
• Citations: 44
• Influential citations: 5
• Summary: This study clarifies the role of the A12T mutation in NGPS patients and demonstrates that ectopic expression of the mutant protein induces the NGPS cellular phenotype, while the protein localizes normally to the nuclear envelope.
• Evidence snippets:
• Snippet 1 (score: 0.494) > BackgroundPremature aging syndromes recapitulate many aspects of natural aging and provide an insight into this phenomenon at a molecular and cellular level. The progeria syndromes appear to cause rapid aging through disruption of normal nuclear structure. Recently, a coding mutation (c.34G > A [p.A12T]) in the Barrier to Autointegration Factor 1 (BANF1) gene was identified as the genetic basis of Néstor-Guillermo Progeria syndrome (NGPS). This mutation was described to cause instability in the BANF1 protein, causing a disruption of the nuclear envelope structure.ResultsHere we demonstrate that the BANF1 A12T protein is indeed correctly folded, stable and that the observed phenotype, is likely due to the disruption of the DNA binding surface of the A12T mutant. We demonstrate, using biochemical assays, that the BANF1 A12T protein is impaired in its ability to bind DNA while its interaction with nuclear envelope proteins is unperturbed. Consistent with this, we demonstrate that ectopic expression of the mutant protein induces the NGPS cellular phenotype, while the protein localizes normally to the nuclear envelope.ConclusionsOur study clarifies the role of the A12T mutation in NGPS patients, which will be of importance for understanding the development of the disease.

[8] Premature aging in genetic diseases: what conclusions can be drawn for physiological aging

• Authors: Filip Milosic, M. Hengstschläger, S. Osmanagic-Myers
• Year: 2024
• Venue: Frontiers in Aging
• URL: https://www.semanticscholar.org/paper/fa5a769be9b5d59cf2afdf1e36142ff50dc53fc6
• DOI: 10.3389/fragi.2023.1327833
• PMID: 38481648
• PMCID: 10933081
• Citations: 12
• Summary: This review will focus on primary causes of well-investigated premature aging diseases Hutchinson-Gilford progeria syndrome, Werner syndrome, and Cockayne syndrome and for each provide an overview of reported aging hallmarks to elucidate resemblance to physiological aging on the mechanistic level and in the context of characteristic age-related diseases.
• Evidence snippets:
• Snippet 1 (score: 0.490) > Progeroid syndromes show premature or accelerated features of aging in specific tissues with disease characteristics more or less accurately resembling corresponding age-related diseases in the elderly. According to previous reports (Carrero et al., 2016) the majority of progeroid syndromes may be subdivided into two categories depending on the molecular function of affected proteins. The first category comprises progeroid syndromes with gene mutations encoding proteins with important function for nuclear envelope stability and organization such as Hutchinson-Gilford progeria syndrome (HGPS), atypical progeria syndromes (APS), mandibuloacral dysplasia type A and B (MADA, MADB), restrictive dermopathy (RD) and Nestor-Guillermo progeria syndrome (NGPS). The components of the first category may be submerged according to affected genes to three groups: i) HGPS, APS and MADA with mutations in LMNA gene, ii) MADB and RD involving mutations in ZMPSTE24 gene and iii) NGPS with mutations in BANF1 gene (Figure 1; reviewed in (Foo et al., 2019)). The second category of progeroid syndromes comprises genes involved in DNA damage repair pathways such as trichothiodystrophy (TTD), xeroderma pigmentosum (XP), Cockayne syndrome (CS), Werner syndrome (WS), Bloom syndrome (BS), Rothmund-Thomson syndrome (RTS), Nijmegen breakage syndrome (NBS), Ataxia telangiectasia (AT) and Fanconi anemia (FA). According to types of DNA damage repair pathway affected, the second class of progeroid syndromes may be again further submerged into three categories: i) global genome (GG) and transcription-coupled (TC) nucleotide excision pathway (NER), (ii) double-strand break repair (DSBR) and iii) interstrand DNA crosslink link repair (ICLR) pathway (Figure 1; see Box 1; reviewed in (Carrero et al., 2016;Fiesco-Roa et al., 2022;Niedernhofer et al., 2011)).

[9] Lipodystrophic Laminopathies: From Dunnigan Disease to Progeroid Syndromes

• Authors: E. Díaz-López, S. Sánchez-Iglesias, Ana I Castro, Silvia Cobelo-Gómez, Teresa Prado-Moraña et al.
• Year: 2024
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/3eeaf2518f47d96c75f6164d8c9c52f00b9f4f4a
• DOI: 10.3390/ijms25179324
• PMID: 39273270
• PMCID: 11395136
• Citations: 2
• Summary: The present review aims to gather the molecular basis of adipose tissue impairment in lipodystrophic laminopathies, their main clinical aspects and recent therapeutic strategies, and summarises the key aspects for their differential diagnosis.
• Evidence snippets:
• Snippet 1 (score: 0.490) > Lipodystrophic laminopathies are a group of ultra-rare disorders characterised by the presence of pathogenic variants in the same gene (LMNA) and other related genes, along with an impaired adipose tissue pattern and other features that are specific of each of these disorders. The most fascinating traits include their complex genotype-phenotype associations and clinical heterogeneity, ranging from Dunnigan disease, in which the most relevant feature is precisely adipose tissue dysfunction and lipodystrophy, to the other laminopathies affecting adipose tissue, which are also characterised by the presence of signs of premature ageing (Hutchinson Gilford-progeria syndrome, LMNA-atypical progeroid syndrome, mandibuloacral dysplasia types A and B, Nestor-Guillermo progeria syndrome, LMNA-associated cardiocutaneous progeria). This raises several questions when it comes to understanding how variants in the same gene can lead to similar adipose tissue disturbances and, at the same time, to such heterogeneous phenotypes and variable degrees of metabolic abnormalities. The present review aims to gather the molecular basis of adipose tissue impairment in lipodystrophic laminopathies, their main clinical aspects and recent therapeutic strategies. In addition, it also summarises the key aspects for their differential diagnosis.

[10] Hutchinson–Gilford progeria syndrome: unraveling the genetic basis, symptoms, and advancements in therapeutic approaches

• Authors: Akhil Arun, A. R. Nath, Bonny Thankachan, M. K. Unnikrishnan
• Year: 2024
• Venue: Therapeutic Advances in Rare Disease
• URL: https://www.semanticscholar.org/paper/c8779a55f2e2a90033c9ae94b822691bdee9d829
• DOI: 10.1177/26330040241305144
• PMID: 39691184
• PMCID: 11650505
• Citations: 3
• Summary: From the genetic underpinnings involving the LMNA gene to the myriad of symptoms affecting various organ systems, the article illuminates the pathophysiology and disease progression of HGPS.
• Evidence snippets:
• Snippet 1 (score: 0.490) > Hutchinson–Gilford Progeria syndrome (HGPS) serves as a prominent model for Progeroid syndromes, a group of rare genetic disorders characterized by accelerated aging. This review explores the genetic basis, clinical presentation, and complications of HGPS. HGPS is caused by mutations in the LMNA gene, resulting in the production of a defective structural protein, prelamin A. This protein contains a “CAAX” motif, where C represents cysteine, and its abnormal processing is central to the disease’s pathology. HGPS leads to multiple organ systems being affected, including cardiovascular, skeletal, neurological, and dermatological systems, causing severe disability and increased mortality. Cardiovascular issues are particularly significant in HGPS and are crucial for developing therapeutic strategies. Recent advances in treatment modalities offer promise for managing HGPS. Farnesyltransferase inhibitors and genetic interventions, such as CRISPR-Cas9, have shown potential in mitigating progerin-associated symptoms, with encouraging results observed in preclinical and clinical studies. Additionally, emerging therapies such as rapamycin, sulforaphane, and MG132 hold promise in targeting underlying disease mechanisms. Comprehensive management approaches, including growth hormone therapy, retinoids, and dental care, are emphasized to enhance overall patient well-being. Despite progress, further research is essential to unravel the complex pathophysiology of Progeroid syndromes and develop effective treatments. Continued focus on therapies that address progerin accumulation and its downstream effects is vital for improving patient care and outcomes for individuals affected by HGPS and related disorders. This review highlights ongoing efforts to understand and combat Progeroid syndromes, aiming to alleviate the burdens imposed by these debilitating conditions. Plain language summary Progeroid syndromes: unraveling the genetic basis, multifaceted symptoms, and advancements in therapeutic approaches This comprehensive review delves into the intricate landscape of Progeroid Syndromes, focusing on the Hutchinson-Gilford Progeria Syndrome (HGPS) and its atypical forms. From the genetic underpinnings involving the LMNA gene to the myriad of symptoms affecting various organ systems, the article illuminates the pathophysiology and disease progression of HGP

[11] The Potential of iPSCs for the Treatment of Premature Aging Disorders

• Authors: C. Compagnucci, E. Bertini
• Year: 2017
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/581917de0fd4d572ad6df509124da8c3de3e0c3c
• DOI: 10.3390/ijms18112350
• PMID: 29112121
• PMCID: 5713319
• Citations: 12
• Influential citations: 2
• Summary: Modeling premature aging with induced pluripotent stem cells (iPSCs) offers the possibility to study these disorders during self-renewal and differentiation into relevant cell types, and allows researchers to understand pathophysiological mechanisms and enables the performance of drug screenings.
• Evidence snippets:
• Snippet 1 (score: 0.489) > Premature aging disorders including Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome, are a group of rare monogenic diseases leading to reduced lifespan of the patients. Importantly, these disorders mimic several features of physiological aging. Despite the interest on the study of these diseases, the underlying biological mechanisms remain unknown and no treatment is available. Recent studies on HGPS (due to mutations of the LMNA gene encoding for the nucleoskeletal proteins lamin A/C) have reported disruptions in cellular and molecular mechanisms modulating genomic stability and stem cell populations, thus giving the nuclear lamina a relevant function in nuclear organization, epigenetic regulation and in the maintenance of the stem cell pool. In this context, modeling premature aging with induced pluripotent stem cells (iPSCs) offers the possibility to study these disorders during self-renewal and differentiation into relevant cell types. iPSCs generated by cellular reprogramming from adult somatic cells allows researchers to understand pathophysiological mechanisms and enables the performance of drug screenings. Moreover, the recent development of precision genome editing offers the possibility to study the complex mechanisms underlying senescence and the possibility to correct disease phenotypes, paving the way for future therapeutic interventions.

[12] Case report: Focal segmental glomerulosclerosis in a pediatric atypical progeroid syndrome

• Authors: S. Jang, Y. Ahn, J. Ko, J. Ko, So-Yeo Lim et al.
• Year: 2022
• Venue: Frontiers in Pediatrics
• URL: https://www.semanticscholar.org/paper/12563169af125b3399f8b7c3ec50f150b384ed59
• DOI: 10.3389/fped.2022.1032653
• PMID: 36389384
• PMCID: 9660256
• Citations: 2
• Summary: This is the first pediatric report of FSGS in an APS patient with confirmed LMNA defect, who manifested progeroid features, lipodystrophy, HCMP with heart valve dysfunction, and steatohepatitis and suggests that screening for proteinuric nephropathy is essential for managing APS patients since childhood.
• Evidence snippets:
• Snippet 1 (score: 0.485) > Progeroid syndromes are a group of rare genetic disorders characterized by clinical features that mimic physiologic aging. Progeroid syndromes share similar clinical features such as hair loss, short stature, skin tightness, cardiovascular diseases, and osteoporosis. However, the underlying mechanism can vary according to the causative gene (1). The progeroid syndrome can be classified into two groups according to its molecular pathophysiology: alterations in components of the nuclear envelope and mutations in genes involved in DNA-repair pathways (1,2). The nuclear envelope component involved in progeroid syndrome is the nuclear lamina, a thin protein meshwork between chromatin and the inner nuclear membrane (3,4), composed of lamins. Lamins contribute to the maintenance of nuclear shape and structure, chromatin organization, and other aspects of nuclear metabolism by interacting with regulatory molecules (5)(6)(7)(8). Lamin A and lamin C (encoded by LMNA, MIM 150330) are widely expressed in somatic cells, and diverse LMNA mutations cause various disorders, laminopathies, including diseases affecting striated and cardiac muscle, lipodystrophy syndromes such as familial partial lipodystrophy (FPLD), peripheral neuropathy, and premature aging (progeroid syndromes) (9,10). > Among the laminopathies, FPLD encompasses abnormal fat distribution and insulin resistance disorders. FPLD type 2 (Dunnigan-type, MIM 151660) is known to be caused by LMNA mutation and is characterized by the progressive lipoatrophy of the limbs, buttocks, and trunk sparing the neck and face. Metabolic alterations are common and cardiovascular comorbidities, and hepatic steatosis is often reported (11). Hutchinson-Gilford progeria syndrome (HGPS, MIM 176670) is another form of laminopathy, an early-onset premature aging disorder. It typically presents at 1-2 years of age with severe growth retardation, lipodystrophy, and skeletal and cardiovascular features (12, 13). The average life span is 13 years (12,14,15).

[13] Towards delineating the chain of events that cause premature senescence in the accelerated aging syndrome Hutchinson–Gilford progeria (HGPS)

• Authors: O. Dreesen
• Year: 2020
• Venue: Biochemical Society Transactions
• URL: https://www.semanticscholar.org/paper/9bbab2589f03196bffb3200714c702493973cdae
• DOI: 10.1042/BST20190882
• PMID: 32539085
• PMCID: 7329345
• Citations: 21
• Influential citations: 1
• Summary: A model on how progerin-induced phenotypes may be temporally and mechanistically linked is presented, highlighting some key findings and present a model for how these different phenotypes are causally and Mechanistically linked.
• Evidence snippets:
• Snippet 1 (score: 0.484) > Aging can be defined as a gradual deterioration of cell and tissue function, resulting in an elevated risk of developing a large number of chronic illnesses. These include cardiovascular disease, diabetes, decreased cognitive and hearing ability, neurodegenerative diseases, and loss of bone and muscle mass. Aging is also correlated with an elevated cancer risk. On a cellular level, increased levels of DNA damage, genomic instability, epigenetic alterations including loss of heterochromatin, telomere shortening, mitochondrial dysfunction, impaired nutrient sensing, loss of proteostasis and permanent growth arrest (senescence) are all aging-associated phenomena [1]. However, given the complexity of the aging phenotype, and the ethical and practical limitations of longitudinal studies, little is known about how all of these 'hallmarks of aging' are causally connected. Progeroid syndromes, which are rare premature aging disorders, may, however, offer a unique window on to the mechanisms that contribute to human physiological aging [2][3][4][5]. Progeria patients exhibit characteristic features of normal aging. Typically, these are variously represented by cardiovascular disease, osteoporosis, lipodystrophy, alopecia and aberrant skin pigmentation. Depending upon the type and severity of the particular syndrome, patients may succumb as early as in their mid-teens or may survive until their fifth decade. Progeroid syndromes can be classified into two main groups: The first group is caused by defects in DNA repair pathways or impaired telomere maintenance and includes Werner syndrome (WS), xeroderma pigmentosum (XP), Bloom syndrome (BS), Nijmegen breakage syndrome (NBS), Cockayne Syndrome (CS), Rothmund-Thomson syndrome (RTS), ataxia telangiectasia (AT), Fanconi anemia (FA), dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson syndrome (HHS). The second group is caused by mutations in components of the nuclear lamina and is represented by Hutchinson-Gilford progeria syndrome (HGPS), restrictive dermopathy (RD), Néstor-Guillermo progeria syndrome (NGPS) and man

[14] Induced Pluripotent Stem Cells Reveal Functional Differences Between Drugs Currently Investigated in Patients With Hutchinson‐Gilford Progeria Syndrome

• Authors: Sophie Blondel, Anne-Laure Jaskowiak, A. Egesipe, A. Le Corf, C. Navarro et al.
• Year: 2014
• Venue: STEM CELLS Translational Medicine
• URL: https://www.semanticscholar.org/paper/6bebf680724d94acfe17685f59078288e7e03557
• DOI: 10.5966/sctm.2013-0168
• PMID: 24598781
• Citations: 47
• Summary: A systematic comparative study of the three main treatments currently administered or proposed to progeria‐affected children, namely, a farnesyltransferase inhibitor, the combination of an aminobisphosphonate and a statin, and the macrolide antibiotic rapamycin reveals the complexity of the modes of action of different drugs, and underscores the use of induced pluripotent stem cell derivatives as a critical and powerful tool for standardized, comparative pharmacological studies.
• Evidence snippets:
• Snippet 1 (score: 0.484) > Hutchinson‐Gilford progeria syndrome is a rare congenital disease characterized by premature aging in children. Identification of the mutation and related molecular mechanisms has rapidly led to independent clinical trials testing different marketed drugs with a preclinically documented impact on those mechanisms. However, the extensive functional effects of those drugs remain essentially unexplored. We have undertaken a systematic comparative study of the three main treatments currently administered or proposed to progeria‐affected children, namely, a farnesyltransferase inhibitor, the combination of an aminobisphosphonate and a statin (zoledronate and pravastatin), and the macrolide antibiotic rapamycin. This work was based on the assumption that mesodermal stem cells, which are derived from Hutchinson‐Gilford progeria syndrome‐induced pluripotent stem cells expressing major defects associated with the disease, may be instrumental to revealing such effects. Whereas all three treatments significantly improved misshapen cell nuclei typically associated with progeria, differences were observed in terms of functional improvement in prelamin A farnesylation, progerin expression, defective cell proliferation, premature osteogenic differentiation, and ATP production. Finally, we have evaluated the effect of the different drug combinations on this cellular model. This study revealed no additional benefit compared with single‐drug treatments, whereas a cytostatic effect equivalent to that of a farnesyltransferase inhibitor alone was systematically observed. Altogether, these results reveal the complexity of the modes of action of different drugs, even when they have been selected on the basis of a similar mechanistic hypothesis, and underscore the use of induced pluripotent stem cell derivatives as a critical and powerful tool for standardized, comparative pharmacological studies.
• Snippet 2 (score: 0.467) > Since the discovery of the molecular mechanisms underlying Hutchinson-Gilford progeria syndrome (HGPS) (OMIM no. 176670), three independent clinical trials have been proposed to treat the patients affected with this accelerated aging disorder: lonafarnib (ClinicalTrials.gov identifier NCT00425607) [1], pravastatin and zoledronate (ClinicalTrials.gov identifier NCT00731016), and their combination (ClinicalTrials.gov identifier NCT00916747). Although some patients are currently treated with these drugs, little is known regarding each of their specific effects on different cell defects observed in progeria. In this study, we have taken advantage of the unique potential of induced pluripotent stem (iPS) cells to address that issue. > Progeria is a rare genetic disorder caused by a point mutation in the LMNA gene that leads to the production and accumulation of a truncated form of lamin A called "progerin" [2,3]. This toxic form of lamin cannot be terminally matured and thus causes disruption of the nuclear structure, defects in DNA repair processes, and other molecular defects associated with premature aging [4]. The disease manifests itself in a set of symptoms that includes growth delay, loss of body fat, osteoporosis, and atherosclerosis leading to premature death [5,6]. Based on the identification of the toxic mechanism leading progeria to be associated with the accumulation of misprocessed farnesylated progerin, two therapeutic strategies have been investigated. Farnesyltransferase inhibitors (FTIs) have been assayed following the restoration of some defects both in vitro and in progeroid animal models [7,8]. The recently published results of this clinical trial indicate the partial clinical benefits of an FTI, lonafarnib, although several adverse effects have been reported [1]. In parallel, because of the previously described antiproliferative effect of FTIs on cancer cells [9], through the activation of an alternative prenylation pathway called "geranylgeranylation," another clinical trial has been initiated.

[15] Hutchinson-Gilford Progeria Syndrome: A Literature Review

• Authors: Aselah Lamis, S. W. Siddiqui, T. Ashok, Nassar Patni, Mahejabeen Fatima et al.
• Year: 2022
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/31c44653445af57fa1c5e9fa25a701ba0c207405
• DOI: 10.7759/cureus.28629
• PMID: 36196312
• PMCID: 9524302
• Citations: 24
• Summary: The understanding of the molecular pathways by which progerin expression leads to HGPS is discussed and how the advanced therapy options for HGPS patients can help us understand and treat the condition is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.481) > Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging condition that involves genetic mutations, resulting in debilitating phenotypic features. The present state of knowledge on the molecular pathways that contribute to the pathophysiology of HGPS and the techniques being tested in vitro and in vivo to combat progerin toxicity have been discussed here. Nuclear morphological abnormalities, dysregulated gene expression, DNA repair deficiencies, telomere shortening, and genomic instability are all caused by progerin accumulation, all of which impair cellular proliferative capability. In addition, HGPS cells and preclinical animal models have revealed new information about the disease's molecular and cellular pathways and putative mechanisms involved in normal aging. This article has discussed the understanding of the molecular pathways by which progerin expression leads to HGPS and how the advanced therapy options for HGPS patients can help us understand and treat the condition.

[16] Therapeutic strategies targeting cellular senescence for cancer and other diseases

• Authors: Xuebing Wang, Takeshi Fukumoto, Ken-ichi Noma
• Year: 2024
• Venue: Journal of Biochemistry
• URL: https://www.semanticscholar.org/paper/25dd21718b1e4e45d3a38b1afd6a7cbd97ddb0fa
• DOI: 10.1093/jb/mvae015
• PMID: 38366629
• PMCID: 11058315
• Citations: 17
• Summary: This review outlines senescence inducers and the general characteristics of senescent cells, and describes a series of senolytic agents and their utilization in therapeutic strategies.
• Evidence snippets:
• Snippet 1 (score: 0.479) > In addition to cancer, cellular senescence has both beneficial and detrimental effects in many aging-related diseases (6,64). Some diseases that present with fibrosis in organs such as the liver, skin, kidneys and heart, and conditions, such as atherosclerosis and pulmonary hypertension, may benefit from senescence (6). In noncancerous hepatic fibrosis, SASP factors produced by senescent cells contribute to extracellular matrix degradation, and immune cells are attracted to the microenvironment to remove senescent hepatic stellate cells, thereby mitigating disease progression (6,65). > Certain diseases are promoted by detrimental effects of physiological and pathological senescence (6,64). Physiological senescence-associated diseases include some lifestyle-related diseases such as type 2 diabetes, agingrelated diseases such as sarcopenia and osteoporosis, and neurodegenerative diseases such as Alzheimer's disease (6,64). For instance, senescent cells tend to accumulate in the adipose tissues of diabetic mice, contributing to insulin resistance (66). Additionally, human geriatric satellite cells in the muscles exhibit senescence tendencies, which accounts for the loss of muscle regenerative potential in sarcopenia (67). > Pathological senescence-associated diseases are closely associated with premature aging syndromes caused by genetic variations or mutations in genes encoding nuclear envelope proteins, DNA repair enzymes and telomere maintenance factors (64). For instance, Hutchinson-Gilford progeria syndrome (HGPS) is caused by a heterozygous point mutation in lamin A (68). Patients with HGPS have several aging-associated characteristics shortly after birth, including alopecia and loss of subcutaneous fat and skeletal muscles (69). Preclinical evidence shows that the loss of lamin A causes the accumulation of senescent cells and accelerates aging phenotypes in mice (70). Furthermore, other pathological senescenceassociated diseases, such as Nestor-Guillermo progeria syndrome and atypical Werner syndrome, are caused by mutations in genes encoding the nuclear envelope architecture (64).

[17] Case report: A novel splice-site mutation of MTX2 gene caused mandibuloacral dysplasia progeroid syndrome: the first report from China and literature review

• Authors: Xiaohui Fu, Shuli Chen, Xiao Huang, Qinghua Lu, Yunfei Cui et al.
• Year: 2024
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/322120e4efe3e1d1bb56a403d62c170883f16b7f
• DOI: 10.3389/fendo.2024.1345067
• PMID: 38544690
• PMCID: 10965776
• Citations: 1
• Summary: This is the first case of MAD syndrome caused by mutations in MTX2 gene reported in the Chinese population, and the report of this patient expands the spectrum of MTX2 mutations.
• Evidence snippets:
• Snippet 1 (score: 0.478) > Nestor-Guillermo Progeria Syndrome (NGPS) was first described and diagnosed in 2011 by Cabanillas R et al., with biallelic pathogenic variants in the BANF1 gene (7). The product encoded by the BANF1 gene is required for the reaggregation of lamin A during the remodeling of the nuclear envelope at the end of mitosis (7). Although the causative genes for several of the above syndromes are different, they are all thought to be associated with toxic accumulation of either prelamin A or lamin A/C. > In 2013, Weedon et al. identified a mandibular hypoplasia, deafness, and lipodystrophy syndrome (MDPL) caused by mutations in POLD1 gene, which encodes the catalytic subunit (p125) of DNA polymerase d(POLd) (8). The catalytic subunit is responsible for synthesizing the lagging strand DNA during DNA replication with both 5′-to 3′-polymerase activity and 3′-to 5′exonuclease activity (9). Pold is involved in DNA replication and maintains genomic stability (9). The p125 mutation leads to reduced genomic stability, cellular senescence, and apoptosis, which may be the pathogenic mechanism of MDPL (9,10). In contrast to other progeria syndromes, MDPL is characterized by early-onset hearing loss. > T h e n o v e l M A D p r o g e r o i d s y n d r o m e ( M A D a M : Mandibuloacral dysplasia associated to MTX2) reported in this study was first described in 2020 by Elouej et al., due to recessive mutations in MTX2 encoding Metaxin-2 (MTX2), an outer mitochondrial membrane (OMM) protein (11). MADaM is clinically characterized by mandibuloacral dysplasia, generalized lipodystrophy, hypotonia, acro osteolysis, skin abnormalities, renal impairment, and cardiovascular system damage such as hypertension and left ventricular hypertrophy.

[18] 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)

• Authors: Natnicha Pongbangli, Kannika Pitipakorn, S. Jai-aue, P. Sirijanchune, Sorawit Pongpittayut et al.
• Year: 2021
• Venue: The American Journal of Case Reports
• URL: https://www.semanticscholar.org/paper/95a1c05c782729f6e01dd0d65c242cd5aba36d22
• DOI: 10.12659/AJCR.928969
• PMID: 33414362
• PMCID: 7805248
• Citations: 2
• Summary: This 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) is rare in that most patients do not live beyond 13 years of age.
• Evidence snippets:
• Snippet 1 (score: 0.467) > We reported the case of a 13-year-old boy from Thailand with Hutchinson-Gilford progeria syndrome with coronary artery and aortic calcification and NSTEMI. Because the mutation status in the LMNA gene was not available for testing in Thailand, the diagnosis of HGPS was based on the age at onset of disease and the presence of typical phenotypic characteristics. > The differential diagnosis of premature aging diseases includes Wiedemann-Rautenstrauch syndrome, also known as neonatal progeroid syndrome. For this diagnosis, the signs and symptoms of aging must present during the neonatal period. The second differential diagnosis is Werner syndrome, also known as adult progeria. These clinical conditions of premature aging begin during the teens or early adulthood. Progeria is the one of premature aging diseases in which the patients usually appear normal at birth. The clinical manifestations are expressed within the first year of life, as in our case [23,24]. > Probable mechanisms of progerin-induced arteriosclerosis were previously reported [25]. A mutation of the Lamin A gene produces nuclear instability and dysregulation of the affected gene expression function, and DNA repair induces cellular senescence [16,26]. The accumulation of un-repairable DNA damage in progeria is caused by mitochondrial reactive oxygen species (ROS)-mediated cell damage and the loss of antioxidant capacity [27][28][29][30][31]. The effect of gene mutation results in loss of vascular smooth-muscle cells and adventitial fibroblast dysfunction [32]. The abnormalities in nuclear morphologic features and function cause cellular stiffening [33][34][35][36]. Cell death encourages extracellular matrix growth in the dense vascular walls. The excessive vascular calcification found in progeria is mainly caused by the loss of pyrophosphate synthesis due to ROS-induced mitochondrial dysfunction [37]. The vascular calcification promotes osteogenic differentiation of vascular smooth-muscle cells [38]. > Patients are affected by decreased creation and production of extracellular pyrophosphate [37], which is generally a strong inhibitor of vascular calcification [39].

Notes

• This provider combines search_papers_by_relevance with snippet_search.
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