Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Genetics

  • 436 Articles
  • 2 Posts
  • ← Previous
  • 1
  • 2
  • 3
  • …
  • 43
  • 44
  • Next →
The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity
Maud Maillard, … , Min Ni, Jun J. Yang
Maud Maillard, … , Min Ni, Jun J. Yang
Published July 15, 2025
Citation Information: J Clin Invest. 2025;135(14):e190443. https://doi.org/10.1172/JCI190443.
View: Text | PDF

The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity

  • Text
  • PDF
Abstract

Thiopurines are anticancer agents used for the treatment of leukemia and autoimmune diseases. These purine analogs are characterized by a narrow therapeutic index because of the risk of myelosuppression. With the discovery of NUDIX hydrolase 15 (NUDT15) as a major modulator of thiopurine metabolism and toxicity, we sought to comprehensively examine all members of the NUDIX hydrolase family for their effect on the pharmacologic effects of thiopurine. By performing a NUDIX-targeted CRISPR/Cas9 screen in leukemia cells, we identified NUDT5, whose depletion led to drastic thiopurine resistance. NUDT5 deficiency resulted in a nearly complete depletion of active metabolites of thiopurine and the loss of thioguanine incorporation into DNA. Mechanistically, NUDT5 deletion resulted in substantial alteration in purine nucleotide biosynthesis, as determined by steady-state metabolomics profiling. Stable isotope tracing demonstrated that the loss of NUDT5 was linked to a marked suppression of the purine salvage pathway but with minimal effects on purine de novo synthesis. Finally, we comprehensively identified germline genetic variants in NUDT5 associated with thiopurine-induced myelosuppression in 582 children with acute lymphoblastic leukemia. Collectively, these results pointed to NUDT5 as a key regulator of the thiopurine response primarily through its effects on purine homeostasis, highlighting its potential to inform individualized thiopurine therapy.

Authors

Maud Maillard, Rina Nishii, Hieu S. Vu, Kashi R. Bhattarai, Wenjian Yang, Jing Li, Ute Hofmann, Daniel Savic, Smita Bhatia, Matthias Schwab, Min Ni, Jun J. Yang

×

The GLYT1 inhibitor bitopertin mitigates erythroid PPIX production and liver disease in erythroid protoporphyria
Sarah Ducamp, … , Brian MacDonald, Paul J. Schmidt
Sarah Ducamp, … , Brian MacDonald, Paul J. Schmidt
Published July 15, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI181875.
View: Text | PDF

The GLYT1 inhibitor bitopertin mitigates erythroid PPIX production and liver disease in erythroid protoporphyria

  • Text
  • PDF
Abstract

Erythropoietic protoporphyria (EPP) is a genetic disorder typically resulting from decreased ferrochelatase (FECH) activity, the last enzyme in heme biosynthesis. Patients with X-linked protoporphyria (XLPP) have an overlapping phenotype caused by increased activity of 5-aminolevulinic acid synthase 2 (ALAS2), the first enzyme in erythroid heme synthesis. In both cases, protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in plasma and tissues. Patients develop acute phototoxicity reactions upon brief exposure to sunlight. Some also suffer from chronic liver disease, and a small fraction develop acute cholestatic liver failure. Therapeutic options are limited, and none, save hematopoietic stem cell transplantation, directly targets erythroid PPIX accumulation. Bitopertin is an investigational orally available small molecule inhibitor of the erythroid cell surface glycine transporter GLYT1. We establish the bitopertin PPIX inhibitory half-maximal effective concentration in a human erythroblast EPP model and confirm a marked reduction of PPIX in erythroblasts derived from EPP patients. We demonstrate that bitopertin also reduces erythrocyte and plasma PPIX accumulation in vivo in mouse models of both EPP and XLPP. Finally, the reduction in erythroid PPIX ameliorates liver disease in the EPP mouse model. Altogether, these data support the development of bitopertin to treat patients with EPP or XLPP.

Authors

Sarah Ducamp, Min Wu, Juan Putra, Dean R. Campagna, Yi Xiang, Vu Hong, Matthew M. Heeney, Amy K. Dickey, Rebecca K. Leaf, Mark D. Fleming, Brian MacDonald, Paul J. Schmidt

×

Mutations in spliceosomal gene SNW1 cause neurodevelopment disorders with microcephaly
Lei Ji, … , Shan Bian, Xiao Mao
Lei Ji, … , Shan Bian, Xiao Mao
Published July 3, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI186119.
View: Text | PDF

Mutations in spliceosomal gene SNW1 cause neurodevelopment disorders with microcephaly

  • Text
  • PDF
Abstract

The spliceosome is a critical cellular machinery responsible for pre-mRNA splicing, essential for the proper expression of genes. Mutations in its core components are increasingly linked to neurodevelopmental disorders, such as primary microcephaly. Here, we investigated the role of SNW1, a spliceosomal protein, in splicing integrity and neurodevelopment. We identified nine heterozygous mutations in the SNW1 gene in patients presenting with primary microcephaly. These mutations impaired SNW1's interactions with core spliceosomal proteins, leading to defective RNA splicing and reduced protein functionality. Using Drosophila melanogaster and human embryonic stem cell-derived cerebral organoids models, we demonstrated that SNW1 depletion resulted in significant reductions in neural stem cell proliferation and increased apoptosis. RNA-sequencing revealed disrupted alternative splicing, especially skipping exons, and altered expression of neurodevelopment-associated genes (CENPE, MEF2C, and NRXN2). Our findings provide crucial insights into the molecular mechanisms by which SNW1 dysfunction contributes to neurodevelopmental disorders and underscore the importance of proper spliceosome function in brain development.

Authors

Lei Ji, Jin Yan, Nicole A. Losurdo, Hua Wang, Liangjie Liu, Keyi Li, Zhen Liu, Zhenming Guo, Jing Xu, Adriana Bibo, Decheng Ren, Ke Yang, Yingying Luo, Fengping Yang, Gui Wang, Zhenglong Xiang, Yuan Wang, Huaizhe Zhan, Hu Pan, Juanli Hu, Jianmin Zhong, Rami Abou Jamra, Pia Zacher, Luciana Musante, Flavio Faletra, Paola Costa, Caterina Zanus, Nathalie Couque, Lyse Ruaud, Anna Maria Cueto-González, Hector San Nicolas Fernández, Eduardo Tizzano, Núria Martínez Gil, Xiaorong Liu, Weiping Liao, Layal Abi Farraj, Alden Y. Huang, Liying Zhang, Aparna Murali, Esther Schmuel, Christina S. Han, Kayla King, Weiyue Gu, Pengchao Wang, Kai Li, Nichole Link, Guang He, Shan Bian, Xiao Mao

×

A haploinsufficiency restoration strategy corrects neurobehavioral deficits in Nf1+/– mice
Su Jung Park, … , Steven P. Angus, D. Wade Clapp
Su Jung Park, … , Steven P. Angus, D. Wade Clapp
Published July 1, 2025
Citation Information: J Clin Invest. 2025;135(13):e188932. https://doi.org/10.1172/JCI188932.
View: Text | PDF

A haploinsufficiency restoration strategy corrects neurobehavioral deficits in Nf1+/– mice

  • Text
  • PDF
Abstract

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations of the NF1 tumor suppressor gene resulting in the loss of function of neurofibromin, a GTPase-activating protein (GAP) for Ras. While the malignant manifestations of NF1 are associated with loss of heterozygosity of the residual WT allele, the nonmalignant neurodevelopmental sequelae, including autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD) are prevalent morbidities that occur in the setting of neurofibromin haploinsufficiency. We reasoned that augmenting endogenous levels of WT neurofibromin could serve as a potential therapeutic strategy to correct the neurodevelopmental manifestations of NF1. Here, we used a combination of genetic screening and genetically engineered murine models to identify a role for the F-box protein FBXW11 as a regulator of neurofibromin degradation. Disruption of Fbxw11, through germline mutation or targeted genetic manipulation in the nucleus accumbens, increased neurofibromin levels, suppressed Ras-dependent ERK phosphorylation, and corrected social learning deficits and impulsive behaviors in male Nf1+/– mice. Our results demonstrate that preventing the degradation of neurofibromin is a feasible and effective approach to ameliorate the neurodevelopmental phenotypes in a haploinsufficient disease model.

Authors

Su Jung Park, Jodi L. Lukkes, Ka-Kui Chan, Hayley P. Drozd, Callie B. Burgin, Shaomin Qian, Morgan McKenzie Sullivan, Cesar Gabriel Guevara, Nolen Cunningham, Stephanie Arenas, Makenna A. Collins, Jacob Zucker, JinHee Won, Abbi Smith, Li Jiang, Dana K. Mitchell, Steven D. Rhodes, Steven P. Angus, D. Wade Clapp

×

The human glucocorticoid receptor variant rs6190 increases blood cholesterol and promotes atherosclerosis
Hima Bindu Durumutla, … , David Y. Hui, Mattia Quattrocelli
Hima Bindu Durumutla, … , David Y. Hui, Mattia Quattrocelli
Published July 1, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI190180.
View: Text | PDF

The human glucocorticoid receptor variant rs6190 increases blood cholesterol and promotes atherosclerosis

  • Text
  • PDF
Abstract

Elevated cholesterol poses cardiovascular risks. The glucocorticoid receptor (GR) harbors a still undefined role in cholesterol regulation. Here, we report that a coding single nucleotide polymorphism (SNP) in the gene en-coding the GR, rs6190, associated with increased cholesterol in women according to UK Biobank and All Of Us datasets. In SNP-genocopying mice, we found that the SNP enhanced hepatic GR activity to transactivate Pcsk9 and Bhlhe40, negative regulators of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) re-ceptors respectively. In mice, the SNP was sufficient to elevate circulating cholesterol across all lipoprotein frac-tions and the risk and severity of atherosclerotic lesions on the pro-atherogenic hAPOE*2/*2 background. The SNP effect on atherosclerosis was blocked by in vivo liver knockdown of Pcsk9 and Bhlhe40. Also, corti-costerone and testosterone were protective against the mutant GR program in cholesterol and atherosclerosis in male mice, while the SNP effect was additive to estrogen loss in females. Remarkably, we found that the mu-tant GR program was conserved in human hepatocyte-like cells using CRISPR-engineered, SNP-genocopying human induced pluripotent stem cells (hiPSCs). Taken together, our study leverages a non-rare human variant to uncover a novel GR-dependent mechanism contributing to atherogenic risk, particularly in women.

Authors

Hima Bindu Durumutla, April Haller, Greta Noble, Ashok Daniel Prabakaran, Kevin McFarland, Hannah Latimer, Akanksha Rajput, Olukunle Akinborewa, Bahram Namjou-Khales, David Y. Hui, Mattia Quattrocelli

×

BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature-positive castration-resistant prostate cancer
Shipra Shukla, … , Ping Chi, Yu Chen
Shipra Shukla, … , Ping Chi, Yu Chen
Published June 24, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI180378.
View: Text | PDF

BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature-positive castration-resistant prostate cancer

  • Text
  • PDF
Abstract

A subgroup (~20-30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by two GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlates with adverse clinical outcomes to androgen receptor signaling inhibitor treatment and shorter overall survival. Bromo- and extra-terminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, while AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi.

Authors

Shipra Shukla, Dan Li, Woo Hyun Cho, Dana M. Schoeps, Holly M. Nguyen, Jennifer L. Conner, Marjorie L. Roskes, Anisha Tehim, Gabriella Bayshtok, Mohini R. Pachai, Juan Yan, Nicholas A. Teri, Eric Campeau, Sarah Attwell, Patrick Trojer, Irina Ostrovnaya, Anuradha Gopalan, Ekta Khurana, Eva Corey, Ping Chi, Yu Chen

×

Biallelic variants in SREK1 downregulating SNORD115 and SNORD116 cause a Prader-Willi-like syndrome
Sadia Saeed, … , Philippe Froguel, Giles S.H. Yeo
Sadia Saeed, … , Philippe Froguel, Giles S.H. Yeo
Published June 23, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI191008.
View: Text | PDF

Biallelic variants in SREK1 downregulating SNORD115 and SNORD116 cause a Prader-Willi-like syndrome

  • Text
  • PDF
Abstract

Up to 10% of patients with severe early-onset obesity carry pathogenic variants in known obesity-related genes, mostly affecting the leptin-melanocortin pathway. Studying children with severe obesity from consanguineous populations provides a unique opportunity to uncover novel molecular mechanisms. Using whole-exome sequencing, followed by a rigorous analytical and filtration strategy, we identified three different homozygous missense variants in SREK1 (encoding Splicing Regulatory glutamic acid and lysine rich protein) in Pakistani children with severe obesity, from three unrelated consanguineous pedigrees. The wild type SREK1 gene of human induced pluripotent stem cell (iPSC)-derived hypothalamic neurons was individually replaced by each of the three variants and the impact of these changes on global gene expression was studied. Neurons expressing the two variants in the SREK1 RNA recognition domain p.P95L and p.T194M, but not the C-terminally located p.E601K, had markedly reduced expression of the small nucleolar RNA clusters SNORD115 and SNORD116, deficiency of which has been implicated in Prader-Willi syndrome (PWS). In addition to hyperphagic obesity the carriers of these two variants had other features of PWS, such as neonatal hypotonia. In conclusion, homozygous variants in SREK1 result in a subtype of severe early onset obesity sharing features with PWS.

Authors

Sadia Saeed, Anna-Maria Siegert, YC Loraine Tung, Roohia Khanam, Qasim M. Janjua, Jaida Manzoor, Mehdi Derhourhi, Bénédicte Toussaint, Brian Y. H. Lam, Sherine Awad, Emmanuel Vaillant, Emmanuel Buse Falay, Souhila Amanzougarene, Hina Ayesha, Waqas Imran Khan, Nosheen Ramzan, Vladimir Saudek, Stephen O'Rahilly, Anthony P. Goldstone, Muhammad Arslan, Amélie Bonnefond, Philippe Froguel, Giles S.H. Yeo

×

Neuraminidase 1 secondary deficiency contributes to CNS pathology in neurological mucopolysaccharidoses via brain proteins hypersialylation
TianMeng Xu, … , Domenico Garozzo, Alexey V. Pshezhetsky
TianMeng Xu, … , Domenico Garozzo, Alexey V. Pshezhetsky
Published June 20, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI177430.
View: Text | PDF

Neuraminidase 1 secondary deficiency contributes to CNS pathology in neurological mucopolysaccharidoses via brain proteins hypersialylation

  • Text
  • PDF
Abstract

Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III and VII, associated with lysosomal accumulation of heparan sulphate (HS), manifest with neurological deterioration and currently lack effective treatments. We report that neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of neurological MPS patients and mouse models but not in neurological lysosomal disorders without HS storage. Accumulated HS disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A (CTSA), β-galactosidase (GLB1) and glucosamine-6-sulfate sulfatase (GALNS) leading to NEU1 deficiency and partial GLB1 and GALNS deficiencies in cortical tissues and iPSC-derived cortical neurons of neurological MPS patients. Increased sialylation of N-linked glycans in brains of MPS patients and mice implicated insufficient processing of sialylated glycans, except for polysialic acid. Correction of NEU1 activity in MPS IIIC mice by lentiviral gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioural traits, and reduced levels of excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1/PSD95-positive puncta in cortical iPSC-derived MPS IIIA neurons. Our results demonstrate that HS-induced secondary NEU1 deficiency and aberrant sialylation of brain glycoproteins constitute what we believe to be a novel pathological pathway in neurological MPS spectrum crucially contributing to CNS pathology.

Authors

TianMeng Xu, Rachel Heon-Roberts, Travis Moore, Patricia Dubot, Xuefang Pan, Tianlin Guo, Christopher W. Cairo, Rebecca J. Holley, Brian Bigger, Thomas M. Durcan, Thierry Levade, Jerôme Ausseil, Bénédicte Amilhon, Alexei Gorelik, Bhushan Nagar, Shaukat Khan, Shunji Tomatsu, Luisa Sturiale, Angelo Palmigiano, Iris Röckle, Hauke Thiesler, Herbert Hildebrandt, Domenico Garozzo, Alexey V. Pshezhetsky

×

Cross-species efficacy of AAV-mediated ARSA replacement for Metachromatic Leukodystrophy
Shyam Ramachandran, … , Martin Goulet, Christian Mueller
Shyam Ramachandran, … , Martin Goulet, Christian Mueller
Published June 19, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI185001.
View: Text | PDF

Cross-species efficacy of AAV-mediated ARSA replacement for Metachromatic Leukodystrophy

  • Text
  • PDF
Abstract

Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder caused by mutations in the arylsulfatase A (ARSA) gene, resulting in lower sulfatase activity and the toxic accumulation of sulfatides in the central and peripheral nervous system. Children account for 70% of cases and become progressively disabled with death occurring within 10 years of disease onset. Gene therapy approaches to restore ARSA expression via adeno-associated viral vectors (AAV) have been promising but hampered by limited brain biodistribution. We report the development of an engineered capsid AAV.GMU01, demonstrating superior biodistribution and transgene expression in the central nervous system of non-human primates (NHPs). Next, we show that AAV.GMU01-ARSA treated MLD mice exhibit persistent, normal levels of sulfatase activity and a concomitant reduction in toxic sulfatides. Treated mice also show a reduction in MLD-associated pathology and auditory dysfunction. Lastly, we demonstrate that treatment with AAV.GMU01-ARSA in NHPs is well-tolerated and results in potentially therapeutic ARSA expression in the brain. In summary, we propose AAV.GMU01-ARSA mediated gene replacement as a clinically viable approach to achieve broad and therapeutic levels of ARSA.

Authors

Shyam Ramachandran, Jeffery Ardinger, Jie Bu, MiAngela Ramos, Lilu Guo, Dhiman Ghosh, Mahmud Hossain, Shih-Ching Chou, Yao Chen, Erik Wischhof, Swathi Ayloo, Roger Trullo, Yuxia Luo, Jessica M. Hogestyn, Daniel M. DuBreuil, Emily Crosier, Johanna G. Flyer-Adams, Amy M. Richards, Michael Tsabar, Giorgio Gaglia, Shelley Nass, Bindu Nambiar, Denise Woodcock, Catherine O'Riordan, Qi Tang, Bradford Elmer, Bailin Zhang, Martin Goulet, Christian Mueller

×

Clonal hematopoiesis detection by simultaneous assessment of peripheral blood mononuclear cells, blood plasma, and saliva
Caitlin M. Stewart, … , Ross L. Levine, Luis A. Diaz, Jr.
Caitlin M. Stewart, … , Ross L. Levine, Luis A. Diaz, Jr.
Published June 19, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI191256.
View: Text | PDF

Clonal hematopoiesis detection by simultaneous assessment of peripheral blood mononuclear cells, blood plasma, and saliva

  • Text
  • PDF
Abstract

Authors

Caitlin M. Stewart, Sonya Parpart-Li, James R. White, Mitesh Patel, Oliver Artz, Michael B. Foote, Erika Gedvilaite, Michelle F. Lamendola-Essel, Drew Gerber, Rohini Bhattacharya, Justin M. Haseltine, Kety Huberman, Kelly L. Bolton, Ross L. Levine, Luis A. Diaz, Jr.

×
  • ← Previous
  • 1
  • 2
  • 3
  • …
  • 43
  • 44
  • Next →
A hop, exon skip, and a jump for muscular dystrophy
Quan Gao and colleagues developed an exon skipping strategy that generates a truncated, functional γ-sarcoglycan protein and improves defects in muscular dystrophy models…
Published October 12, 2015
Scientific Show StopperGenetics

A curve in the spine
Shunmoogum Patten and colleagues identify variants of POC5 that are associated with idiopathic scoliosis…
Published February 2, 2015
Scientific Show StopperGenetics
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts