[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-440615-105":59,"doc-detail-440615-en":129},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":122,"head_meta":124,"extra_data":126,"updated_unix":128},105,"en","transcriptional-profiling-of-hutchinson-gilford-progeria-patients-identifies-primary-target-pathways-of-progerin","Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin","","Hutchinson Gilford Progeria Syndrome (HGPS) is an ultra-rare pediatric premature aging disorder driven by a point mutation in LMNA that produces a dominant-negative progerin isoform of lamin A. Clinical relevance of previously implicated pathways and inter-patient gene-expression heterogeneity are tested through transcriptomic profiling of a comprehensive patient cohort. Misexpression affects multiple signaling routes, the Unfolded Protein Response (UPR), and mesodermal cell fate specification, with limited variability across patients. Comparing patient profiles with an inducible HGPS cell model identifies primary progerin target pathways.",{"@graph":69,"@context":121},[70,84,104],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/transcriptional-profiling-of-hutchinson-gilford-progeria-patients-identifies-primary-target-pathways-of-progerin/440615/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":98,"encodingFormat":97,"isAccessibleForFree":99,"interactionStatistic":100},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/transcriptional-profiling-of-hutchinson-gilford-progeria-patients-identifies-primary-target-pathways-of-progerin/440615.png","ImageObject",300,407,{"name":92,"@type":93},"acoobca","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-29",true,{"@type":101,"interactionType":102,"userInteractionCount":4},"InteractionCounter",{"@type":103},"ViewAction",{"@type":105,"mainEntity":106},"FAQPage",[107,113,117],{"name":108,"@type":109,"acceptedAnswer":110},"What causes Hutchinson-Gilford progeria syndrome in this study?","Question",{"text":111,"@type":112},"The disease is caused by a point mutation in the LMNA gene that leads to production of a dominant-negative progerin isoform, disrupting nuclear architecture and cellular functions.","Answer",{"name":114,"@type":109,"acceptedAnswer":115},"Which pathways show misexpression in HGPS patients?",{"text":116,"@type":112},"The study reports misexpression of multiple signaling pathways, the Unfolded Protein Response (UPR), and mesodermal cell fate specification, with the major pathways affected in most patients.",{"name":118,"@type":109,"acceptedAnswer":119},"How were the primary target pathways of progerin identified?",{"text":120,"@type":112},"Primary target pathways were determined by comparing the patients’ transcriptomes with an inducible HGPS cell model to link dysregulated expression patterns to progerin activity.","https://schema.org",{"og:url":83,"og:type":123,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":125,"canonical":83},"index,follow",{"doc_id":127,"site_id":62},440615,1790692692,{"code":4,"msg":5,"data":130},{"doc_id":127,"user_id":131,"nickname":92,"user_avatar":132,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":4,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":138,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":139,"faqs":140,"seo_title":141,"seo_description":67,"update_tm":128,"read_time":142},3985747870733,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","NUCLEUS  \n2026, VOL. 17, NO. 1, 2611484 [https://doi.org/10.1080/19491034.2025.261](https://doi.org/10.1080/19491034.2025.261)1484  \nRESEARCH ARTICLE     \nTranscriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin  \nSandra Vidak a*, Sohyoung Kimb*, and Tom Misteli a  \naCell Biology of Genomes, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; bHormone Action and Oncogenesis Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA  \nABSTRACT  \nHutchinson Gilford Progeria Syndrome (HGPS) is an ultra-rare pediatric premature aging disorder. It is caused by a point mutation in the LMNA gene leading to the production of the dominantnegative progerin isoform of the nuclear envelope protein lamin A. Most of the mechanistic insights into the disease have come from studies using cellular or mouse models of HGPS. To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, we performed transcriptomic analysis of a comprehensive set of HGPS patients. We find misexpression of several cellular pathways, including multiple signaling pathways, the Unfolded Protein Response (UPR) and mesodermal cell fate specification. Variability amongst individual patients was limited, with misregulation of the major pathways observed in most patients. Comparing the transcriptome of patients with aninducible HGPS cell model, we also identified the primary target pathways of the disease-causing progerin protein.  \nARTICLE HISTORY  \nReceived 22 September 2025 Revised 11 December 2025 Accepted 27 December 2025  \nKEYWORDS  \nHutchinson-Gilford progeria syndrome; pathway analysis; progerin; RNA-seq; transcriptional profiling  \nIntroduction  \nHutchinson-Gilford Progeria Syndrome (HGPS) isan extremely rare genetic disorder characterized by segmental premature aging with an incidence of approximately 1 in 4–8 million live births [ 1,2] . Although infants appear phenotypically normal at birth, clinical manifestations typically emerge between 9 and 12 months of age and include growth retardation, short stature, alopecia, joint contractures, osteolysis, and progressive lipodystrophy [ 1,3–5] . As the disease progresses, patients experience arthritis and cardiovascular pathology, including accelerated atherosclerosis and arterial stiffening, with death typically occurring from myocardial infarction or stroke around a mean age of 14.5 years [6–9] .  \nClassic HGPS is caused by a de novo heterozygous point mutation (c.1824C >T; G608G) in exon 11 of the LMNA gene, which encodes the nuclear lamina proteins lamin A and C [ 10, 11] . Although  \nthe disease-causing mutation does not alter the predicted amino acid sequence of lamin A, it activates a cryptic splice donor site in the LMNA premRNA, resulting in the production of a truncated lamin A isoform referred as progerin [ 10, 11] . This aberrant isoform lacks 50 amino acids at the C-terminus, including the cleavage site for the ZMPSTE24 metalloprotease, thereby retaining a farnesylated C-terminal motif that permanently anchors progerin to the inner nuclear membrane [2, 12, 13] . Progerin exerts dominant-negative effects that disrupt nuclear architecture and impair critical cellular functions. Its accumulation leads to nuclear blebbing, loss of heterochromatin, impaired DNA repair, altered gene expression, and defects in mechanotransduction [ 14–16] . Additionally, progerin aggregates at the nuclear periphery sequester essential regulatory proteins, such as the oxidative stress response factor NRF2 and molecular chaperones in the endoplasmic  \nCONTACT Sandra Vidak  [sandra.vidak@nih.gov](sandra.vidak@nih.gov); Tom Misteli  mistelit@mail. nih.gov  Cell Biology of Genomes, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA  \n*Authors contributed equally.  \n Supplemental data for this article can be ac","cbCaiiBGqJp8bWY0","https://ap.wps.com/l/cbCaiiBGqJp8bWY0","pdf",3681184,"English","# Introduction\n## Hutchinson-Gilford Progeria Syndrome overview\n## LMNA mutation and progerin mechanism\n# Results and Conclusions\n## Transcriptomic analysis across HGPS patients\n## Identified misregulated pathways and progerin targets","[{\"question\":\"What causes Hutchinson-Gilford progeria syndrome in this study?\",\"answer\":\"The disease is caused by a point mutation in the LMNA gene that leads to production of a dominant-negative progerin isoform, disrupting nuclear architecture and cellular functions.\"},{\"question\":\"Which pathways show misexpression in HGPS patients?\",\"answer\":\"The study reports misexpression of multiple signaling pathways, the Unfolded Protein Response (UPR), and mesodermal cell fate specification, with the major pathways affected in most patients.\"},{\"question\":\"How were the primary target pathways of progerin identified?\",\"answer\":\"Primary target pathways were determined by comparing the patients’ transcriptomes with an inducible HGPS cell model to link dysregulated expression patterns to progerin activity.\"}]","Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin | PDF",48]