Search Results (30)

Background/Objectives: Hutchinson–Gilford progeria syndrome (HGPS) is a rare and fatal genetic disease caused by a silent mutation in the LMNA gene, leading to the production of progerin, a defective prelamin A variant. Progerin accumulation disrupts nuclear integrity, alters chromatin organization, and drives systemic cellular dysfunction. While autophagy and inflammation are key dysregulated pathways in HGPS, the role of microRNAs (miRNAs) in these processes remains poorly understood. Methods: We performed an extensive literature review to identify miRNAs involved in autophagy and inflammation. Through stem-loop RT-qPCR in aging HGPS and control fibroblast strains, we identified significant miRNAs and focused on the most prominent one, miR-181a-5p, for in-depth analysis. We validated our in vitro findings with miRNA expression studies in skin biopsies from an HGPS mouse model and conducted functional assays in human fibroblasts, including immunofluorescence staining, β-Galactosidase assay, qPCR, and Western blot analysis. Transfection studies were performed using an miR-181a-5p mimic and its inhibitor. Results: We identified miR-181a-5p as a critical regulator of premature senescence in HGPS. miR-181a-5p was significantly upregulated in HGPS fibroblasts and an HGPS mouse model, correlating with Sirtuin 1 (SIRT1) suppression and induction of senescence. Additionally, we demonstrated that TGFβ1 induced miR-181a-5p expression, linking inflammation to miRNA-mediated senescence. Inhibiting miR-181a-5p restored SIRT1 levels, increased proliferation, and alleviated senescence in HGPS fibroblasts, supporting its functional relevance in disease progression. Conclusions: These findings highlight the important role of miR-181a-5p in premature aging and suggest its potential as a therapeutic target for modulating senescence in progeroid syndromes. Full article

This review starts off with the first germline homozygous variants of the Nucleoporin 98 gene (NUP98) in siblings whose clinical presentation recalls Rothmund–Thomson (RTS) and Werner (WS) syndromes. The progeroid phenotype caused by a gene associated with haematological malignancies and neurodegenerative disorders primed the search for interplay between caretakers involved in genome instability syndromes and Nuclear Pore Complex (NPC) components. In the context of basic information on NPC architecture and functions, we discuss the studies on the interdependence of caretakers and gatekeepers in WS and Hereditary Fibrosing Poikiloderma (POIKTMP), both entering in differential diagnosis with RTS. In WS, the WRN/WRNIP complex interacts with nucleoporins of the Y-complex and NDC1 altering NPC architecture. In POIKTMP, the mutated FAM111B, recruited by the Y-complex’s SEC13 and NUP96, interacts with several Nups safeguarding NPC structure. The linkage of both defective caretakers to the NPC highlights the attempt to activate a repair hub at the nuclear periphery to restore the DNA damage. The two separate WS and POIKTMP syndromes are drawn close by the interaction of their damage sensors with the NPC and by the shared hallmark of short fragile telomeres disclosing a major role of both caretakers in telomere maintenance. Full article

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. Full article

Werner syndrome (WS) is an autosomal recessive disease caused by loss of function of WRN. WS is a segmental progeroid disease and shows early onset or increased frequency of many characteristics of normal aging. WRN possesses helicase, annealing, strand exchange, and exonuclease activities and acts on a variety of DNA substrates, even complex replication and recombination intermediates. Here, we review the genetics, biochemistry, and probably physiological functions of the WRN protein. Although its precise role is unclear, evidence suggests WRN plays a role in pathways that respond to replication stress and maintain genome stability particularly in telomeric regions. Full article

James German’s work to establish the natural history and cancer risk associated with Bloom syndrome (BS) has had a strong influence on the generation of scientists and clinicians working to understand other RECQ deficiencies and heritable cancer predisposition syndromes. I summarize work by us and others below, inspired by James German’s precedents with BS, to understand and compare BS with the other heritable RECQ deficiency syndromes with a focus on Werner syndrome (WS). What we know, unanswered questions and new opportunities are discussed, as are potential ways to treat or modify WS-associated disease mechanisms and pathways. Full article

This review article critically examines the pivotal role of chromatin organization in gene regulation, cellular differentiation, disease progression and aging. It explores the dynamic between the euchromatin and heterochromatin, coded by a complex array of histone modifications that orchestrate essential cellular processes. We discuss the pathological impacts of chromatin state misregulation, particularly in cancer and accelerated aging conditions such as progeroid syndromes, and highlight the innovative role of epigenetic therapies and artificial intelligence (AI) in comprehending and harnessing the histone code toward personalized medicine. In the context of aging, this review explores the use of AI and advanced machine learning (ML) algorithms to parse vast biological datasets, leading to the development of predictive models for epigenetic modifications and providing a framework for understanding complex regulatory mechanisms, such as those governing cell identity genes. It supports innovative platforms like CEFCIG for high-accuracy predictions and tools like GridGO for tailored ChIP-Seq analysis, which are vital for deciphering the epigenetic landscape. The review also casts a vision on the prospects of AI and ML in oncology, particularly in the personalization of cancer therapy, including early diagnostics and treatment optimization for diseases like head and neck and colorectal cancers by harnessing computational methods, AI advancements and integrated clinical data for a transformative impact on healthcare outcomes. Full article

Mutations in the LMNA-gene can cause a variety of ‘laminopathies’. These laminopathies are associated with a range of phenotypes, including disorders affecting the adipose tissue, peripheral nerves, the heart, such as dilated cardiomyopathy and conduction system abnormalities, and less commonly, progeroid disorders. This case series describes two families in which two novel LMNA-gene variants were identified, and who presented with an atypical progeroid phenotype with primarily premature aortic and mitral valve stenosis. Interestingly, these families exhibited no clear evidence of multisystem involvement, illustrating the complex role of lamins A/C. Full article

Cockayne syndrome (CS) is a rare autosomal recessive disorder that affects the DNA repair process. It is a progeroid syndrome predisposing patients to accelerated aging and to increased susceptibility to respiratory infections. Here, we studied the immune status of CS patients to determine potential biomarkers associated with pathological aging. CS patients, as well as elderly and young, healthy donors, were enrolled in this study. Complete blood counts for patients and donors were assessed, immune cell subsets were analyzed using flow cytometry, and candidate cytokines were analyzed via multi-analyte ELISArray kits. In CS patients, we noticed a high percentage of lymphocytes, an increased rate of intermediate and non-classical monocytes, and a high level of pro-inflammatory cytokine IL-8. In addition, we identified an increased rate of particular subtypes of T Lymphocyte CD8+ CD28− CD27−, which are senescent T cells. Thus, an inflammatory state was found in CS patients that is similar to that observed in the elderly donors and is associated with an immunosenescence status in both groups. This could explain the CS patients’ increased susceptibility to infections, which is partly due to an aging-associated inflammation process. Full article

Bi-allelic pathogenic variations within POLR3A have been associated with a spectrum of hereditary disorders. Among these, a less frequently observed condition is Wiedemann–Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome. This syndrome typically manifests neonatally and is characterized by growth retardation, evident generalized lipodystrophy with distinctively localized fat accumulations, sparse scalp hair, and atypical facial features. Our objective was to elucidate the underlying molecular mechanisms of Wiedemann–Rautenstrauch syndrome (WRS). In this study, we present a clinical case of a 7-year-old female patient diagnosed with WRS. Utilizing whole-exome sequencing (WES), we identified a novel missense variant c.3677T>C (p.Leu1226Pro) in the POLR3A gene (NM_007055.4) alongside two cis intronic variants c.1909+22G>A and c.3337-11T>C. Via the analysis of mRNA derived from fibroblasts, we reconfirmed the splicing-affecting nature of the c.3337-11T>C variant. Furthermore, our investigation led to the reclassification of the c.3677T>C (p.Leu1226Pro) variant as a likely pathogenic variant. Therefore, this is the first case demonstrating the molecular genetics of a patient with Wiedemann–Rautenstrauch syndrome from the Russian Federation. A limited number of clinical cases have been documented until this moment; therefore, broadening the linkage between phenotype and molecular changes in the POLR3A gene will significantly contribute to the comprehensive understanding of the molecular basis of POLR3A-related disorders. Full article

The LMNA gene encodes lamin A and lamin C, which play important roles in nuclear organization. Pathogenic variants in LMNA cause laminopathies, a group of disorders with diverse phenotypes. There are two main groups of disease-causing variants: missense variants affecting dimerization and intermolecular interactions, and heterozygous substitutions activating cryptic splice sites. These variants lead to different disorders, such as dilated cardiomyopathy and Hutchinson–Gilford progeria (HGP). Among these, the phenotypic terms for LMNA-associated cardiocutaneous progeria syndrome (LCPS), which does not alter lamin A processing and has an older age of onset, have been described. Here, we present the workup of an LMNA variant of uncertain significance, NM_170707.2 c. 4G>A, p.(Glu2Lys), in a 36-year-old female with severe calcific aortic stenosis, a calcified mitral valve, premature aging, and a family history of similar symptoms. Due to the uncertainty of in silico predictions for this variant, an assessment of nuclear morphology was performed using the immunocytochemistry of stable cell lines to indicate whether the p.(Glu2Lys) had a similar pathogenic mechanism as a previously described pathogenic variant associated with LCPS, p.Asp300Gly. Indirect immunofluorescence analysis of nuclei from stable cell lines showed abnormal morphology, including lobulation and occasional ringed nuclei. Relative to the controls, p.Glu2Lys and p.Asp300Gly nuclei had significantly (p < 0.001) smaller average nuclear areas than controls (mean = 0.10 units, SD = 0.06 for p.Glu2Lys; and mean = 0.09 units, SD = 0.05 for p.Asp300Gly versus mean = 0.12, SD = 0.05 for WT). After functional studies and segregation studies, this variant was upgraded to likely pathogenic. In summary, our findings suggest that p.Glu2Lys impacts nuclear morphology in a manner comparable to what was observed in p.Asp300Gly cells, indicating that the variant is the likely cause of the LCPS segregating within this family. Full article

The likely pathogenic variant c.407A>T p.Asp136Val of the LMNA gene has been recently described in a young woman presenting with atypical progeroid syndrome, associated with severe aortic valve stenosis. We further describe the cardiovascular involvement associated with the syndrome in her family. We identified seven members with a general presentation suggestive of progeroid syndrome. All of them presented heart conduction abnormalities: degenerative cardiac diseases such as coronary artery disease (two subjects) and aortic stenosis (three subjects) occurred in the 3rd–5th decade, and a young patient developed a severe dilated cardiomyopathy, leading to death at 15 years of age. The likely pathogenic variant was found in all the patients who consented to carry out the genetic test. This diverse family cardiologic phenotype emphasizes the complex molecular background at play in lamin-involved cardiac diseases, and the need for early and thorough cardiac evaluations in patients with laminopathic progeroid syndromes. Full article

Human TOR1AIP1 encodes LAP1, a nuclear envelope protein expressed in most human tissues, which has been linked to various biological processes and human diseases. The clinical spectrum of diseases related to mutations in TOR1AIP1 is broad, including muscular dystrophy, congenital myasthenic syndrome, cardiomyopathy, and multisystemic disease with or without progeroid features. Although rare, these recessively inherited disorders often lead to early death or considerable functional impairment. Developing a better understanding of the roles of LAP1 and mutant TOR1AIP1-associated phenotypes is paramount to allow therapeutic development. To facilitate further studies, this review provides an overview of the known interactions of LAP1 and summarizes the evidence for the function of this protein in human health. We then review the mutations in the TOR1AIP1 gene and the clinical and pathological characteristics of subjects with these mutations. Lastly, we discuss challenges to be addressed in the future. Full article

Lamina-associated polypeptide 1 (LAP1) is a ubiquitously expressed inner nuclear membrane protein encoded by TOR1AIP1, and presents as two isoforms in humans, LAP1B and LAP1C. While loss of both isoforms results in a multisystemic progeroid-like syndrome, specific loss of LAP1B causes muscular dystrophy and cardiomyopathy, suggesting that LAP1B has a critical role in striated muscle. To gain more insight into the molecular pathophysiology underlying muscular dystrophy caused by LAP1B, we established a patient-derived fibroblast line that was transdifferentiated into myogenic cells using inducible MyoD expression. Compared to the controls, we observed strongly reduced myogenic differentiation and fusion potentials. Similar defects were observed in the C2C12 murine myoblasts carrying loss-of-function LAP1A/B mutations. Using RNA sequencing, we found that, despite MyoD overexpression and efficient cell cycle exit, transcriptional reprogramming of the LAP1B-deficient cells into the myogenic lineage is impaired with delayed activation of MYOG and muscle-specific genes. Gene set enrichment analyses suggested dysregulations of protein metabolism, extracellular matrix, and chromosome organization. Finally, we found that the LAP1B-deficient cells exhibit nuclear deformations, such as an increased number of micronuclei and altered morphometric parameters. This study uncovers the phenotypic and transcriptomic changes occurring during myoconversion of patient-derived LAP1B-deficient fibroblasts and provides a useful resource to gain insights into the mechanisms implicated in LAP1B-associated nuclear envelopathies. Full article

Progeroid syndromes (PS), including Hutchinson-Gilford Progeria Syndrome (HGPS), are premature and accelerated aging diseases, characterized by clinical features mimicking physiological aging. Most classical HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type lamins. This mutation activates a cryptic splice site, leading to the production of a truncated prelamin A, called prelamin A ∆50 or progerin, that accumulates in HGPS cell nuclei and is a hallmark of the disease. Some patients with PS carry other LMNA mutations and are named “HGPS-like” patients. They produce progerin and/or other truncated prelamin A isoforms (∆35 and ∆90). We previously found that MG132, a proteasome inhibitor, induced progerin clearance in classical HGPS through autophagy activation and splicing regulation. Here, we show that MG132 induces aberrant prelamin A clearance and improves cellular phenotypes in HGPS-like patients’ cells other than those previously described in classical HGPS. These results provide preclinical proof of principle for the use of a promising class of molecules toward a potential therapy for children with HGPS-like or classical HGPS. Full article

Background: Cockayne syndrome (CS) is a rare form of dwarfism that is characterized by progressive premature aging. CS is typically caused by mutations in the excision repair cross-complementing protein group 6 (ERCC6) gene that encodes the CS group B (CSB) protein. Using whole exome sequencing, we recently identified a novel homozygous missense mutation (Leu536Trp) in CSB in a Taiwanese boy with CS. Since the current database (Varsome) interprets this variant as likely pathogenic, we utilized a bioinformatic tool to investigate the impact of Leu536Trp as well as two other variants (Arg453Ter, Asp532Gly) in similar articles on the CSB protein structure stability. Methods: We used iterative threading assembly refinement (I-TASSER) to generate a predictive 3D structure of CSB. We calculated the change of mutation energy after residues substitution on the protein stability using I-TASSER as well as the artificial intelligence program Alphafold. Results: The Asp532Gly variant destabilized both modeled structures, while the Leu536Trp variant showed no effect on I-TASSER’s model but destabilized the Alphafold’s modeled structure. Conclusions: We propose here the first case of CS associated with a novel homozygous missense mutation (Leu536Trp) in CSB. Furthermore, we suggest that the Asp532Gly and Leu536Trp variants are both pathogenic after bioinformatic analysis of protein stability. Full article