The Journal of Clinical Investigation最新文献

{"title":"Carboxypeptidase D deficiency causes hearing loss amenable to treatment.","authors":"Memoona Ramzan,Natalie Ortiz-Vega,Mohammad Faraz Zafeer,Amanda G Lobato,Tahir Atik,Clemer Abad,Nirmal Vadgama,Duygu Duman,Nazım Bozan,Enise Avcı Durmuşalioǧlu,Sunny Greene,Shengru Guo,Suna Tokgöz-Yılmaz,Merve Koç Yekedüz,Fatma Tuba Eminoğlu,Mehmet Aydın,Serhat Seyhan,Ioannis Karakikes,Vladimir Camarena,Maria Camila Robayo,Tijana Canic,Güney Bademci,Gaofeng Wang,Amjad Farooq,Mei-Ling Joiner,Katherina Walz,Daniel F Eberl,Jamal Nasir,R Grace Zhai,Mustafa Tekin","doi":"10.1172/jci192090","DOIUrl":"https://doi.org/10.1172/jci192090","url":null,"abstract":"Genetic factors contributing to hearing loss (HL) are heterogeneous, and effective medical treatments remain limited. We identified three distinct missense variants in CPD, encoding carboxypeptidase D, in five individuals with congenital deafness from three unrelated families, affecting the catalytically active CP-domain2 of this protein. Subsequent analysis of a larger cohort from the 100,000 Genomes Project (100KGP), revealed an enrichment of rare protein-altering CPD variants in individuals with HL. We show that CPD localizes to sensory epithelium and nerve cells in the mouse cochlea, and the enzymatic activity of CPD, crucial for nitric oxide (NO) production through arginine processing, is impaired in affected individuals. The levels of arginine, NO, and cyclic guanosine monophosphate (cGMP) in patient-derived fibroblasts are also decreased, leading to increased oxidative stress and cell death via endoplasmic reticulum stress-mediated mechanisms. Silencing of Cpd in organotypic mouse cochlea cultures leads to increased apoptosis. Finally, Drosophila models of CPD deficiency display defective Johnston's organ, impaired auditory transduction, and sensory and movement abnormalities. Notably, these phenotypes are partially rescued by the supplementation with arginine or sildenafil, a cGMP enhancer. Our findings establish CPD mutations as a cause of congenital HL, highlighting that the NO signaling pathway offers a promising therapeutic avenue.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.","authors":"Cameron McDonald-Hyman,Ethan G Aguilar,Ewoud B Compeer,Michael C Zaiken,Stephanie Y Rhee,Fathima A Mohamed,Jemma H Larson,Michael L Loschi,Christopher Lees,Govindarajan Thangavelu,Margaret L Sleeth,Kyle D Smith,Jennifer S Whangbo,Jerome Ritz,Tim D Sparwasser,Roddy S O'Connor,Peter A Crawford,Jeffrey C Rathmell,Leslie S Kean,Robert Zeiser,Keli L Hippen,Michael L Dustin,Bruce R Blazar","doi":"10.1172/jci182480","DOIUrl":"https://doi.org/10.1172/jci182480","url":null,"abstract":"Regulatory T-cells (Treg) are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Treg predominantly depend upon oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg \"effector\" differentiation, but FAO activity is inhibited by coordinated activity of isoenzymes acetyl-CoA Carboxylase-1 and -2 (ACC1/2). Here, we show that small molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic GVHD. ACC1 inhibition skewed Treg towards an \"effector\" phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg suppressive potency. Ex vivo expanded, ACC1 inhibitor treated human Treg similarly augmented suppressor function as observed with murine Treg. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Five-year analysis of efficacy and safety of a bidirectional AAV gene therapy in Tay-Sachs sheep.","authors":"Toloo Taghian,Jillian Gallagher,Stephanie Bertrand,William C Baker,Kalajan Lopez Mercado,Hector R Benatti,Erin Hall,Yvette Lopez,Abigail McElroy,John T McCarthy,Sanjana Pulaparthi,Deborah Fernau,Samuel Mather,Sophia Esteves,Elise Diffie,Amanda Gross,Hannah G Lahey,Xuntian Jiang,Elizabeth Parsley,Rachael Gately,Rachel Prestigiacomo,Siauna Johnson,Amanda Taylor,Lindsey Bierfeldt,Susan Tuominen,Jennifer Koehler,Guangping Gao,Jun Xie,Qin Su,Robert King,Matthew J Gounis,Vania Anagnostakou,Ajit Puri,Ana Rita Batista,Miguel Sena-Esteves,Douglas R Martin,Heather Gray-Edwards","doi":"10.1172/jci182942","DOIUrl":"https://doi.org/10.1172/jci182942","url":null,"abstract":"Tay-Sachs and Sandhoff disease are fatal neurodegenerative diseases without an effective therapy that are caused by mutations in the HEXA and HEXB genes, respectively. Together they encode the heterodimeric isozyme of hexosaminidase (HexA) that degrades GM2 ganglioside. This report describes a 5 year-long study using a bidirectional AAV9 vector (AAV9-Bic_HexA/HexB) encoding both HEXA and HEXB in the Tay-Sachs sheep model. Bidirectional AAV9 was delivered intravenously or through various cerebral spinal fluid (CSF) delivery routes: intracerebroventricular (ICV), cisterna magna (CM) and lumbar delivery (LIT). The longest survival and best distribution were achieved by multipoint CSF delivery (combined CM, ICV and LIT) with treated animals survived up to 5 years of age (untreated Tay-Sachs animals die ~9 months). Extension in survival was accompanied by lasting improvement in neurological examination and maze testing. Improvement in biomarkers of efficacy including MRI, MR spectroscopy, diffusion tensor imaging as well as CSF levels of GM2 ganglioside and hexosaminidase A (HexA) activity was evident. Post-mortem assessments showed broad HexA distribution, GM2 ganglioside clearance and vector genome distribution, especially in deep brain structures. Therapeutic efficacy documented in this study supports translation of bidirectional vector and multipoint CSF delivery to a clinical trial in Tay-Sachs and Sandhoff disease patients.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ER stress sensor PERK promotes T-cell pathogenicity in GVHD by regulating ER-associated degradation.","authors":"Qiao Cheng,Hee-Jin Choi,Yongxia Wu,Xiaohong Yuan,Allison Pugel,Linlu Tian,Michael Hendrix,Denggang Fu,Reza Alimohammadi,Chen Liu,Xue-Zhong Yu","doi":"10.1172/jci190958","DOIUrl":"https://doi.org/10.1172/jci190958","url":null,"abstract":"Endoplasmic reticulum (ER) stress through IRE1/XBP-1 is implicated in the onset and progression of graft-versus-host disease (GVHD), but the role of ER stress sensor PERK in T-cell allogeneic responses and GVHD remains unexplored. Here, we report that PERK is a key regulator in T-cell allogeneic response and GVHD induction. PERK augments GVHD through increasing Th1 and Th17 population, while reducing Treg differentiation by activating Nrf2 pathway. Genetical deletion or selective inhibition of PERK pharmacologically reduces GVHD while preserving graft-versus-leukemia (GVL) activity. At cellular level, PERK positively regulates CD4+ T-cell pathogenicity, while negatively regulating CD8+ T-cell pathogenicity in the induction of GVHD. At molecular level, PERK interacts with SEL1L and regulates SEL1L expression, leading to augmented T-cell allogeneic responses and GVHD development. In vivo, PERK deficiency in donor T cells alleviate GVHD through ER-associated degradation (ERAD). Furthermore, pharmacological inhibition of PERK with AMG44 significantly suppresses the severity of GVHD induced by murine or human T cells. In summary, our findings validate PERK as a potential therapeutic target for the prevention of GVHD while preserving GVL responses, and uncover the mechanism by which PERK differentially regulates CD4+ versus CD8+ T-cell allogeneic and anti-tumor responses.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"91 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aggregation shifts amyloid-β peptides from synaptogenic to synaptotoxic.","authors":"Alberto Siddu,Silvia Natale,Connie H Wong,Hamidreza Shaye,Thomas C Südhof","doi":"10.1172/jci193407","DOIUrl":"https://doi.org/10.1172/jci193407","url":null,"abstract":"Whether amyloid-β (Aβ) peptides are synaptogenic or synaptotoxic remains a pivotal open question in Alzheimer's disease research. Here, we chronically treated human neurons with precisely controlled concentrations of chemically defined synthetic Aβ40, Aβ42, and Aβ42arctic peptides that exhibit distinct aggregation propensities. Remarkably, chronic exposure of human neurons to free Aβ40 at higher concentrations or to free Aβ42 at lower concentrations potently promoted synapse formation. In contrast, aggregated Aβ42 or Aβ42arctic at higher concentrations were neurotoxic and synaptotoxic. The synaptotoxic effects of Aβ peptides manifested as an initial contraction of the synaptic vesicle cluster followed by synapse loss. Aβ40 and Aβ42 peptides with scrambled or inverted sequences were inactive. Thus, our experiments reveal that Aβ peptides exhibit an aggregation-dependent functional dichotomy that renders them either synaptogenic or synaptotoxic, thereby providing insight into how Aβ peptides straddle a thin line between physiological synapse organization and pathological synapse disruption. Among others, our data suggest that Alzheimer's disease therapies might aim to shift the balance of Aβ peptides from the aggregated to the free state instead of suppressing all Aβ peptides.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"78 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ER stress upregulates S100A11 in steatohepatitis models via epigenetic modifications within the lipotoxicity influenced enhancer.","authors":"P Vineeth Daniel,Hanna L Erickson,Daheui Choi,Feda H Hamdan,Yasuhiko Nakao,Gyanendra Puri,Takahito Nishihara,Yeriel Yoon,Amy S Mauer,Debanjali Dasgupta,Jill Thompson,Alexander Revzin,Harmeet Malhi","doi":"10.1172/jci191074","DOIUrl":"https://doi.org/10.1172/jci191074","url":null,"abstract":"Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by complex interactions between lipotoxicity, ER stress responses, and immune-mediated inflammation. We identified enrichment of the proinflammatory alarmin S100 calcium-binding protein A11 (S100A11) on extracellular vesicles stimulated by palmitate-induced lipotoxic ER stress with concomitant upregulation of hepatocellular S100A11 abundance in an IRE1A-XBP1s dependent manner. We next investigated the epigenetic mechanisms that regulate this stress response. Publicly available human liver ChIP-Seq GEO datasets demonstrated a region of histone H3 lysine 27 (H3K27) acetylation upstream to the S100A11 promoter. H3K27acetylation ChIP-qPCR demonstrated a positive correlation between lipotoxic ER stress and H3K27acetylation of the region, which we termed Lipotoxicity Influenced Enhancer (LIE) domain. CRISPR-mediated repression of the LIE domain reduced palmitate-induced H3K27acetylation and corresponding S100A11 upregulation in Huh7 cells and immortalized mouse hepatocytes. Silencing of the murine LIE in two independent steatohepatitis models demonstrated reduced S100a11 upregulation and attenuated liver injury. We confirmed H3K27acetylation and XBP1s occupancy at the LIE domain in human MASH liver samples and an increase in hepatocyte-derived S100A11-enriched extracellular vesicles in MASH patient plasma. Our studies demonstrate a LIE domain which mediates hepatic S100A11 upregulation. This pathway may be a potential therapeutic target in MASH.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An open letter to the NIH: value and costs in publishing.","authors":"Sarah Jackson,Karen D Guth,John B Hawley,Corinne L Williams,Priscilla Y Hsue,Oliver Eickelberg,Elizabeth M McNally","doi":"10.1172/jci200201","DOIUrl":"https://doi.org/10.1172/jci200201","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allergen-Specific mRNA-Lipid Nanoparticle Therapy for Prevention and Treatment of Experimental Allergy in Mice.","authors":"Yrina Rochman,Michael Kotliar,Andrea M Klingler,Mark Rochman,Mohamad-Gabriel Alameh,Jilian R Melamed,Garrett A Osswald,Julie M Caldwell,Jennifer M Felton,Lydia E Mack,Julie Hargis,Ian P Lewkowich,Artem Barski,Drew Weissman,Marc E Rothenberg","doi":"10.1172/jci194080","DOIUrl":"https://doi.org/10.1172/jci194080","url":null,"abstract":"Allergic diseases have reached epidemic proportions globally, calling attention to the need for better treatment and preventive approaches. Herein, we developed allergen-encoding messenger RNA (mRNA) lipid nanoparticle (LNP) strategies for both therapy and prevention of allergic responses. Immunization with allergen-encoded mRNA-LNPs modulated T cell differentiation, inhibiting the generation of T helper type 2 (Th2) and type 17 (Th17) cells upon allergen exposure in experimental asthma models induced by ovalbumin (OVA), and naturally occurring house dust mite (HDM) and the major HDM allergen Der p1. Allergen-specific mRNA-LNP treatment attenuated clinicopathology in both preventive and established allergy models, including reduction in eosinophilia, mucus production, and airway hypersensitivity, while enhancing production of allergen-specific IgG antibodies and maintaining low IgE levels. Additionally, allergen-specific mRNA-LNP vaccines in mice elicited a CD8+CD38+KLRG- T cell response as seen following SARS-CoV-2 mRNA vaccination in human, underscoring a conserved immune mechanism across species, regardless of the mRNA-encoded protein. Notably, mRNA-LNP vaccination in combination with an mTOR inhibitor reduced the CD8+ T cell response without affecting the vaccine-induced anti-allergic effect in the preventive model of asthma. This technology renders allergen-specific mRNA-LNP therapy as a promising approach for prevention and treatment of allergic diseases.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP10/GSK3B-mediated inhibition of PTEN drives resistance to PI3K inhibitors in breast cancer.","authors":"Nishi Kumari,Sarah Ce Wright,Christopher M Witham,Laia Monserrat,Marta Palafox,John Lalith Charles Richard,Carlotta Costa,Moshe Elkabets,Mark Agostino,Theresa Klemm,Melissa K Eccles,Alexandra Garnham,Ting Wu,Jonas A Nilsson,Nikita Walz,Veena Venugopal,Anthony Cerra,Natali Vasilevski,Stephanie C Bridgeman,Sona Bassi,Azad Saei,Moutaz Helal,Philipp Neundorf,Angela Riedel,Mathias Rosenfeldt,Jespal Gill,Nikolett Pahor,Oliver Hartmann,Jacky Chung,Sachdev S Sidhu,Nina Moderau,Sudhakar Jha,Jordi Rodon,Markus E Diefenbacher,David Komander,Violeta Serra,Pieter Eichhorn","doi":"10.1172/jci180927","DOIUrl":"https://doi.org/10.1172/jci180927","url":null,"abstract":"Activating mutations in PIK3CA, the gene encoding the catalytic p110-alpha subunit of PI3K, are some of the most frequent genomic alterations in breast cancer. Alpelisib, a small-molecule inhibitor that targets p110-alpha, is a recommended drug for patients with PIK3CA-mutant advanced breast cancer. However, clinical success for PI3K inhibitors has been limited by their narrow therapeutic window. The lipid phosphatase PTEN is a potent tumour suppressor and a major negative regulator of the PI3K pathway. Unsurprisingly, inactivating mutations in PTEN correlate with tumour progression and resistance to PI3K inhibition due to persistent PI3K signalling. Here we demonstrate that PI3K inhibition leads rapidly to the inactivation of PTEN. Using a functional genetic screen we show that this effect is mediated by a USP10-GSK3-B signalling axis, in which USP10 stabilizes GSK3-B resulting in GSK3-B-mediated phosphorylation of the C-terminal tail of PTEN. This phosphorylation inhibits PTEN dimerization and thus prevents its activation. Downregulation of GSK3-B or USP10 re-sensitizes PI3K inhibitor resistant breast cancer models and patient derived organoids to PI3K inhibition and induces tumour regression. Our study establishes that enhancing PTEN activity is a new strategy to treat PIK3CA mutant tumours and provides a strong rationale for pursuing USP10 inhibitors in the clinic.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupting Integrator complex subunit INTS6 causes neurodevelopmental disorders and impairs neurogenesis and synapse development.","authors":"Xiaoxia Peng,Xiangbin Jia,Hanying Wang,Jingjing Chen,Xiaolei Zhang,Senwei Tan,Xinyu Duan,Can Qiu,Mengyuan Hu,Haiyan Hou,Ilaria Parenti,Alma Kuechler,Frank J Kaiser,Alicia Renck,Raymond Caylor,Cindy Skinner,Joseph Peeden,Benjamin Cogne,Bertrand Isidor,Sandra Mercier,Gael Nicolas,Anne-Marie Guerrot,Flavio Faletra,Luciana Musante,Lior Cohen,Gaber Bergant,Goran Čuturilo,Borut Peterlin,Andrea Seeley,Kristine Bachman,Julian A Martinez-Agosto,Conny van Ravenswaaij-Arts,Dennis Bos,Katherine H Kim,Tobias Bartolomaeus,Zelia Schmederer,Rami Abou Jamra,Erfan Aref-Eshghi,Wenjing Zhao,Yongyi Zou,Zhengmao Hu,Qian Pan,Faxiang Li,Guodong Chen,Jiada Li,Zhangxue Hu,Kun Xia,Jieqiong Tan,Hui Guo","doi":"10.1172/jci191729","DOIUrl":"https://doi.org/10.1172/jci191729","url":null,"abstract":"The Integrator complex plays essential roles in RNA polymerase II transcription termination and RNA processing. Here, we identify INTS6, a subunit of the Integrator complex, as a novel gene associated with neurodevelopmental disorders (NDDs). Through analysis of large NDD cohorts and international collaborations, we identified 23 families harboring monoallelic likely gene-disruptive or de novo missense variants in INTS6. Phenotypic characterization revealed shared features, including language and motor delays, autism, intellectual disability, and sleep disturbances. Using a nervous-system conditional knockout (cKO) mouse model, we show that Ints6 deficiency disrupts early neurogenesis, cortical lamination, and synaptic development. Ints6 cKO mice displayed a thickened ventricular zone/subventricular zone, thinning of the cortical plate, reduced neuronal differentiation, and increased apoptosis in cortical layer 6. Behavioral assessments of heterozygous mice revealed deficits in social novelty preference, spatial memory, and hyperactivity, mirroring phenotypes observed in individuals with INTS6 variants. Molecular analyses further revealed that INTS6 deficiency alters RNA polymerase II dynamics, disrupts transcriptional regulation, and impairs synaptic gene expression. Treatment with a CDK9 inhibitor (CDK9i) reduced RNAPII phosphorylation, thereby limiting its binding to target genes. Notably, CDK9i reversed neurosphere over-proliferation and rescued the abnormal dendritic spine phenotype caused by Ints6 deficiency. This work advances understanding of INTS-related NDD pathogenesis and highlights potential therapeutic targets for intervention.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}