Genetics
Abstract
SEL1L is a well-known protein in the ER-associated degradation (ERAD) pathway. While it is known to be expressed in platelets, SEL1L has never been shown to play an active role. Here, we present evidence that SEL1L regulates platelet function. We first identified SEL1L through the study of Atypical Equine Thrombasthenia (AET), an autosomal recessive platelet disorder found in thoroughbred horses. A missense variant in SEL1L (c.1810A>G p.Ile604Val) was found in AET-affected horses, which we show is associated with decreased protein expression. SEL1L is intracellular in equine platelets and localizes to the surface upon activation with thrombin. Platelets from homozygous horses exhibited substantially decreased spreading on immobilized collagen. Human megakaryocytes were found to have 2 SEL1L protein isoforms that increase in expression during megakaryopoiesis, although only 1 isoform was delivered to mature platelets. Studies using inducible mouse and constitutive zebrafish KOs demonstrated that SEL1L is necessary for efficient platelet or thrombocyte (fish equivalent) adhesion to sites of endothelial injury. These data reveal a previously undescribed and conserved role for the ERAD pathway in the etiology of AET and platelet function, and GWAS data suggest that it may play a role in human platelet disorders as well.
Authors
Anna R. Dahlgren, Francesca Careddu, Jeffrey W. Norris, Christian A. Di Buduo, Livia Stanger, Reheman Adili, Erin M. Kropp, Qing Li, Michael Holinstat, Ida Biunno, Alessandra Balduini, Fern Tablin, Jordan A. Shavit, Carrie J. Finno
Abstract
Authors
Stephen G. Kaler
Abstract
Authors
Vishal M. Gohil, Michael J. Petris, Francesc Palau
Abstract
BACKGROUND. MASLD has a substantial inherited component. Rare variants in Apolipoprotein B gene (APOB) have been implicated in susceptibility to liver steatosis, but their role in disease progression and outcomes is unclear. METHODS. We investigated APOB rare variants in a case-control cohort of people with advanced MASLD vs. healthy controls (n = 510/261), a family-based study (n = 43 and literature meta-analysis), the Million Veteran Program cohort (MVP, n = 94,885) and the UK Biobank (UKBB, n = 417,657). RESULTS. In the clinical cohort, APOB variants were enriched in people with advanced MASLD (OR 13.8, 95% c.i. 2.7-70.7, P = 0.002) and associated with lower circulating lipids, but higher MASLD activity and fibrosis (P < 0.05). In the family study, APOB variants segregated with hepatic steatosis and fibrosis (P < 0.05). Cross-ancestry meta-analysis of the study cohorts yielded pooled ORs for cirrhosis and hepatocellular carcinoma of 1.82, 95% c.i. 1.33-2.49 and 3.53, 95% c.i. 2.09-5.98, respectively. Variants affecting specifically ApoB100 had a three-fold greater impact on hepatic lipid metabolism compared to those impairing also ApoB48 and were specifically protective against coronary artery disease (P < 0.05). Variants affected cirrhosis risk similarly, but ApoB48/100 had a larger impact on hepatocellular carcinoma (P < 0.05). CONCLUSIONS. Rare APOB variants predispose to advanced MASLD and HCC, with distinct contributions from disrupted VLDL and chylomicrons secretion. These findings highlight the interplay between hepatic and intestinal lipid handling, suggesting that APOB genotyping may enhance MASLD risk stratification and case identification. FUNDING. European Union, Italian Ministry of Health, Swedish Research Council, Veteran health administration, NIH.
Authors
Matteo Mureddu, Serena Pelusi, Oveis Jamialahmadi, Marijana Vujkovic, Lorenzo Miano, Hadi Eidgah Torghabehei, Luisa Ronzoni, Francesco Malvestiti, Marco Saracino, Giulia Periti, Vittoria Moretti, Craig C. Teerlink, Julie A. Lynch, Philip S. Tsao, Josephine P. Johnson, Vincenzo La Mura, Robertino Dilena, Saleh A. Alqahtani, Alessandro Cherubini, Francesco Paolo Russo, Roberta D'Ambrosio, Mirella Fraquelli, Salvatore Petta, Luca Miele, Umberto Vespasiani-Gentilucci, Elisabetta Bugianesi, Rosellina M. Mancina, Paolo Parini, Daniele Prati, Kyong-Mi Chang, Carolin V. Schneider, Stefano Romeo, Luca V.C. Valenti
Abstract
Cervical cancer (CC) remains the fourth leading cause of cancer-related deaths in women globally, with poor prognosis for metastatic and recurrent cases. Although genomic alterations have been extensively characterized, global proteogenomic landscape of the disease is largely under-explored. Here, we present the first genome-wide proteogenomic characterization of CC, analyzing 139 tumor-normal tissue pairs using whole-genome sequencing, transcriptomics, proteomics, and phosphoproteomics. We identified four distinct molecular subtypes with unique clinical outcomes: epithelial-mesenchymal transition (EMT, C1), proliferation (C2), immune response (C3), and epithelial differentiation (C4). A four-protein classifier (CDH13, TP53BP1, NNMT, HSPB1) was developed with strong prognostic and predictive value, particularly for immunotherapy response in subtype C3. Phosphoproteomic profiling uncovered subtype-specific kinase activity, identifying actionable therapeutic targets. Our findings further revealed previously uncharacterized somatic copy number alterations, extrachromosomal DNA landscape, and human-HPV fusion peptides, with implications for genetic heterogeneity and therapeutic targets. This study enhances the understanding of cervical cancer through deeper proteogenomic insights, and facilitates the development of personalized therapeutic strategies to improve patient outcomes.
Authors
Xun Tian, Mansheng Li, Zhi Wang, Tian Fang, Yi Liu, Jin Fang, Lejing Wang, Zhichao Jiang, Xingyu Zhao, Chen Cao, Zhiqiang Yu, Meiying Yang, Songfeng Wu, Yifan Wu, Rui Tian, Hui Wang, Yunping Zhu, Zheng Hu
Abstract
Ceramides are essential skin lipids for maintaining the mammalian skin permeability barrier, which protects against external stimuli. The precursor of epidermal ceramides, glucosylceramides (GlcCer), is synthesized within granular keratinocytes while its precise cellular transport mechanisms remain poorly characterized. Here, we identified three pathogenic variants in the GLTP gene, which encodes glycolipid transfer protein, in five unrelated families with nonsyndromic epidermal differentiation disorder presenting with generalized skin scaling. The biallelic GLTP variants resulted in loss of competent GLTP expression. CRISPR/Cas9-generated Gltp knockout mice exhibited lethal barrier defects, partially recapitulating the clinical features of our patients. We demonstrated that GLTP facilitated GlcCer transport in differentiated keratinocytes, with its deficiency causing impaired GlcCer trafficking and consequent aberrant retention in lysosomes, thereby disrupted lysosome function. The lysosomal dysfunction impaired autophagy flux, resulting in delayed keratinocyte terminal differentiation, which is expected to compromise the skin barrier integrity and ultimate abnormal scaling. Pharmaceutical inhibition of GlcCer synthesis effectively rescued both autophagy and keratinocyte differentiation defects. Our findings establish GLTP as a novel underlying gene for nonsyndromic epidermal differentiation disorders and unravel its essential role in maintaining skin homeostasis during terminal differentiation by mediating epidermal GlcCer transport.
Authors
Zeqiao Zhang, Shimiao Huang, Adam Jackson, Elizabeth A. Jones, Siddharth Banka, Chao Yang, Sisi Zhao, Kunlun Lv, Sha Peng, Zhimiao Lin, Huijun Wang
Abstract
SCN8A encodes the voltage-gated sodium channel Nav1.6, which plays a key role in facilitating neuronal excitability. Mutations in SCN8A, particularly gain-of-function variants, cause SCN8A developmental and epileptic encephalopathy (DEE), a severe epilepsy syndrome characterized by seizures, cognitive dysfunction, movement disorders, and sudden unexpected death in epilepsy (SUDEP). The recurrent SCN8A variant R1872W impairs channel inactivation, causing neuronal hyperexcitability and seizures. Current treatments, including antiseizure medications, are often ineffective for patients with SCN8A DEE, highlighting the need for targeted therapies. We employed base editing to correct the R1872W SCN8A variant. An adenine base editor and guide RNA (SCN8A-ABE) were packaged within dual PhP.eB-adeno-associated viruses (AAVs) and administered to R1872W mice at P2. SCN8A-ABE significantly increased survival of mice expressing R1872W and either reduced seizure incidence and severity or eliminated seizure occurrence. Electrophysiological recordings revealed a rescue of seizure-associated neuronal hyperexcitability and suppression of the pathogenic persistent sodium current (INaP) in treated mice. Comorbidities, including diminished mobility and anxiety-like behaviors, were improved by SCN8A-ABE. These effects were achieved by a 32% absolute reduction in mutant transcripts, accompanied by conversion to SCN8A WT transcripts. Our findings demonstrate base editing as an effective targeted therapeutic approach for SCN8A DEEs by addressing the underlying genetic cause.
Authors
Caeley M. Reever, Alexis R. Boscia, Tyler C.J. Deutsch, Mansi P. Patel, Raquel M. Miralles, Shrinidhi Kittur, Erik J. Fleischel, Atum M.L. Buo, Matthew S. Yorek, Miriam H. Meisler, Charles R. Farber, Manoj K. Patel
Abstract
The regulation of the programmed cell death protein 1 (PD-1) gene, PDCD1, has been widely explored at transcription and posttranslational levels in T cell function and tumor immune evasion. However, the mechanism for PDCD1 dysregulation at the posttranscriptional level remains largely unknown. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a RNA binding protein in a methyltransferase activity–independent manner, which promotes PDCD1 decay with WD repeat domain 77 protein (WDR77) and Argonaute2. Furthermore, the type-I IFN/STAT1 pathway transcriptionally activates PRMT5 and WDR77, thus enhancing PRMT5/WDR77 binding on a conserved AU-rich element of PDCD1 3′ UTR. Functionally, conditional knockout of either PRMT5 or WDR77 in T cells disrupts T cell effector function and sensitizes the tumors to anti–PD-1 therapy. Clinically, PRMT5 and WDR77 expression in tumor-infiltrating T cells are negatively correlated with PDCD1 expression and renders tumors resistant to PD-1–targeted immunotherapy. Moreover, fludarabine targeting STAT1 in combination with anti–PD-1 has a synergetic effect on suppressing tumor growth in mice. Overall, this study reveals that the RNA binding–dependent function of PRMT5 regulates PDCD1 and T cell effector function with WDR77 and identifies potential combinatorial therapeutic strategies for enhancing antitumor efficacy.
Authors
Yinmin Gu, Yongbo Pan, Chang Pan, Qiang Pang, Zhantong Tang, Yiwen Chen, Haojing Zang, Xiaodong Wang, Chang Huang, Qingqing Zhang, Facai Yang, Xiaofeng Zhu, Yibi Zhang, Xujie Zhao, Shan Gao
Abstract
Lipodystrophy syndromes are marked by loss of adipose tissue (AT), which leads to insulin resistance and metabolic syndrome development. We identified a heterozygous nonsense variant in early B cell factor 2 (EBF2) (Chr8:26033143C>A, NM_022659.4: c.493G>T, p.E165X) in a patient with atypical partial lipodystrophy (PLD). The EBF family is crucial for the differentiation and function of various mesenchymal tissues. Through in vitro and in vivo disease models, we discovered that this variant limits adipocyte differentiation and hampers adipose tissue remodeling. Heterozygous knock-in (Ebf2E165X/+) mice showed restricted adipogenesis and defective extracellular matrix (ECM) remodeling during post-weaning and high-fat diet (HFD)-induced adipose tissue expansion. HFD caused abnormal adipocyte hypertrophy, decreased expression of adiponectin and leptin, and glucose intolerance in Ebf2E165X/+ mice. Furthermore, key mitochondrial genes involved in fatty acid metabolism and oxidation were specifically downregulated in the Ebf2E165X/+ adipose tissue. Our results suggest that EBF2 dysfunction driven by this nonsense variant drives disease pathology, establishing a connection between EBF2 disruption and an atypical form of lipodystrophy.
Authors
Maria C. Foss-Freitas, Donatella Gilio, Lynn Pais, Eric D. Buras, Romil Kaul Verma, Melanie O'Leary, Heidi L. Rehm, Carmen Glaze, Kathryn Russell, Andre Monteiro da Rocha, Adam Neidert, Patrick Seale, Miriam S. Udler, Elif A. Oral, Tae-Hwa Chun
Abstract
Atypical dopamine transporter (DAT) deficiency syndrome (DTDS) arises from genetic disruption of DAT function and is characterized by early-onset parkinsonism alongside comorbid psychiatric symptoms. However, the underlying pathobiological processes are largely unknown. Here, we present a mouse model of atypical DTDS based on the patient-derived compound heterozygote genotype, DAT-I312F/D421N+/+. DAT-I312F/D421N+/+ mice exhibited markedly impaired DAT function, leading to widespread changes in dopamine homeostasis, including elevated extracellular dopamine levels, reduced tyrosine hydroxylase and dopamine D1/D2 receptor expression, and decreased evoked dopamine release, mechanistically linked to enhanced tonic D2 autoreceptor inhibition. Fiber photometry measurements revealed disrupted fast striatal dopamine release dynamics, while confocal imaging showed reduced striatal dopaminergic axon fiber density. These neurochemical changes were accompanied by a psychomotor phenotype characterized by hyperlocomotion, enhanced exploration and pronounced clasping. Both amphetamine and anticholinergic treatment ameliorated the aberrant hyperactivity. Notably, amphetamine-induced dopamine release was profoundly blunted in ventral striatum but largely preserved in dorsal striatum, implicating region-specific dopamine release dynamics as a determinant of divergent behavioral and pharmacological responses. Summarized, our findings uncover multiscale dopamine dysfunction that links presynaptic DAT impairment to synaptic and circuit-level disruptions, offering insight into atypical DTDS and the co-occurrence of movement and psychiatric features.
Authors
Freja Herborg, Lisa K. Konrad, Søren H. Jørgensen, Jamila H. Lilja, Benoît Delignat-Lavaud, Leonie P. Posselt, Ciara F. Pugh, Sofie A. Bach, Cecilia F. Ratner, Nora Awadallah, Jose A. Pino, Frida Berlin, Aske L. Ejdrup, Mikkel V. Olesen, Mattias Rickhag, Birgitte Holst, Susana Aznar, Felix P. Mayer, David Woldbye, Gonzalo E. Torres, Louis-Eric Trudeau, Ulrik Gether
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)