Molecular Medicine最新文献

{"title":"Exploring the role of palmitoylation in sepsis: mechanistic insights and future perspectives.","authors":"Susu Cao, Wenyan Xiao, Sinong Pan, Tianfeng Hua, Min Yang","doi":"10.1186/s10020-025-01284-5","DOIUrl":"10.1186/s10020-025-01284-5","url":null,"abstract":"<p><strong>Background: </strong>The palmitoylation system is intricate, multidimensional, and plays a crucial role in various inflammatory and immune-related disorders. Palmitoylation controls protein stability, cargo sorting, signal transmission, as well as cell differentiation and death. Notably, a growing body of studies has highlighted its participation in inflammatory processes, either directly or indirectly, indicating its broad and complex involvement in the development of sepsis. Understanding the mechanisms underlying palmitoylation is essential for advancing research on sepsis. We began this review with a brief summary of research related to sepsis progression. Second, we went over recent studies on palmitoylation. Third, we compiled and described palmitoylation-related alterations in vital molecules or biological processes involved in sepsis. Lastly, we outlined the promising features of palmitoylation and proposed a hopeful outlook for future research in sepsis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"217"},"PeriodicalIF":6.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PARP3 promotes macrophage inflammation via mono ADP ribosylation of Ppia Glu140.","authors":"Runjie Fan, Rongxing Zhu, Xiangxiu Cao, Shuhui Ye, Fengyi Gao, Yue Wu, Wanxin Yao, Guang Liang, Yanmei Zhang","doi":"10.1186/s10020-025-01278-3","DOIUrl":"10.1186/s10020-025-01278-3","url":null,"abstract":"<p><strong>Background: </strong>Acute lung injury (ALI) carries significant mortality with limited targeted therapies. Macrophages drive early inflammatory propagation in ALI, exacerbating pulmonary inflammation. While ADP-ribosylation is a dynamic and reversible post-translational modification (PTM) associated with inflammatory diseases, its role in macrophage-mediated inflammation remains unclear.</p><p><strong>Methods: </strong>Murine ALI model was established via intratracheal instillation with lipopolysaccharide (LPS). The ALI lung tissues and cultured mouse macrophage line (RAW264.7) treated with LPS were used to assess the expression of poly ADP-ribose polymerases (Parps). RNA sequencing (RNA-seq) identified differentially expressed genes (DEGs) following Parp3 knockdown (siParp3) in LPS-stimulated RAW264.7 cells, with subsequent pathway analysis was via transcription factors (TFs) profiling and gene ontology (GO) enrichment. In RAW264.7 cells, Parp3 and peptidyl-prolyl cis-trans isomerase A (Ppia) was modulated by siRNA or plasmid transfection. PARP3-Ppia interaction and ADP-ribosylation were assessed by immunoprecipitation. Modification alterations due to mutations at Ppia modification sites were assessed by immunoprecipitation. Enzyme-linked immune sorbent assay (ELISA) was used to quantify Ppia secretion. A mouse ALI model was used to evaluate the lung-protective and therapeutic effects of PARP3 inhibitor ME0328 by detecting inflammatory cytokines, phosphorylation of p65 and lung histopathology.</p><p><strong>Results: </strong>LPS induced the expression of Parp3 in RAW264.7 cells and ALI lung tissues, correlating with elevated inflammatory cytokines. The 52 overlapping DEGs were mainly enriched in Toll-like receptor (TLR) signaling pathway. PARP3 promoted inflammation via NF-κB activation. ME0328 blocked NF-κB pathway activation in RAW264.7 cells and lung tissues. Immunoprecipitation confirmed that PARP3 interacted with Ppia. Ppia was modified with mono ADP-ribosylation. Ppia-E140 was the most inflammation related modification site. The mutation of E140 inhibited inflammatory response, mono ADP-ribosylation and secretion of Ppia. In vivo, ME0328 reduced inflammatory response, alleviated pulmonary edema and mitigated histopathological damage.</p><p><strong>Conclusions: </strong>We identified the NF-κB as the downstream signaling pathway mediated by Ppia for PARP3 to promote macrophage inflammation. ME0328 alleviated pulmonary inflammation through the NF-κB signaling pathway. Our findings provide evidence that macrophage inflammation is associated with the mono ADP-ribosylation on Ppia. Understanding mono ADP-ribosylation regulation in macrophage from ALI may provide insight into the pro-inflammatory mechanisms and opportunities for effective therapeutic to treat acute lung injury.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"216"},"PeriodicalIF":6.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular detection of hrHPV-induced high-grade squamous intraepithelial lesions of the cervix through a targeted RNA next generation sequencing assay.","authors":"Julia Faillace Thiesen, Elise Jacquemet, Pascal Campagne, Denis Chatelain, Etienne Brochot, Yves-Edouard Herpe, Nolwenn M Dheilly, Fabrice Bouilloux, Bénédicte Rognon, Alexandre Douablin, Guillaume Leboucher, Florent Percher, Marc Eloit, Philippe Pérot","doi":"10.1186/s10020-025-01238-x","DOIUrl":"10.1186/s10020-025-01238-x","url":null,"abstract":"<p><strong>Background: </strong>Cervical cancer screening programs are increasingly relying on sensitive molecular approaches as primary tests to detect high-risk human papillomaviruses (hrHPV), the causative agents of cervix cancer. Although hrHPV infection is a pre-requisite for the development of most precancerous lesions, the mere detection of viral nucleic acids, also present in transient infections, is not specific of the underlying cellular state, resulting in poor positive predictive values (PPV) regarding lesional states. There is a need to increase the specificity of molecular tests for better stratifying individuals at risk of cancer and to adapt follow-up strategies.</p><p><strong>Methods: </strong>HPV-RNA-SEQ, a targeted RNA next generation sequencing assay allowing the detection of up to 16 hrHPV splice events and key human transcripts, has previously shown encouraging PPV for the detection of precancerous lesions. Herein, on 302 patients with normal cytology (NILM, n = 118), low-grade (LSIL, n = 104) or high-grade squamous intraepithelial lesions (HSIL, n = 80), machine learning-based model improvement was applied to reach 2-classes (NILM vs HSIL) or 3-classes (NILM, LSIL, HSIL) predictive models.</p><p><strong>Results: </strong>Linear (elastic net) and nonlinear (random forest) approaches resulted in five 2-class models that detect HSIL vs NILM in a validation set with specificity up to 0.87, well within the range of PPV of other competing RNA-based tests in a screening population.</p><p><strong>Conclusions: </strong>HPV-RNA-SEQ improves the detection of HSIL lesions and has the potential to complete and eventually replace current molecular approaches as a first-line test. Further performance evaluation remains to be done on larger and prospective cohorts.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"215"},"PeriodicalIF":6.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with MASH.","authors":"Yi Chen, Kangjie Xie, Caiyang Chen, Xihui Wang, Chenchen Ma, Zhangxiang Huang, Yingfu Jiao, Weifeng Yu","doi":"10.1186/s10020-025-01275-6","DOIUrl":"10.1186/s10020-025-01275-6","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common chronic liver diseases worldwide, and specific treatment modalities are lacking. Accumulating evidence suggests that hepatic inflammation plays a key role in the progression from hepatic steatosis to MASH. Macrophages, especially anti-inflammatory macrophages, serve as natural immune cells that maintain homeostasis in the immune microenvironment. Here, we aimed to reveal the role of anti-inflammatory macrophages in MASH and investigate the underlying mechanism involved.</p><p><strong>Methods & results: </strong>Extracellular vesicles (EVs) were isolated from the supernatant of anti-inflammatory bone marrow-derived macrophages (BMDMs) by ultracentrifugation, and their protein profile was characterized by liquid chromatography-tandem mass spectrometry (LC‒MS/MS) analysis. Murine hepatocytes were stimulated with palmitic acid (PA) followed by treatment with EVs or oxysterol-binding protein-related protein 8 (ORP8/Osbpl8) shRNA. C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for 3 weeks to establish MASH. The mice were then treated with EVs or shRNA-encoding AAV. In vitro and ex vivo experiments revealed that extracellular vesicles derived from anti-inflammatory BMDMs inhibited inflammatory responses and alleviated lipotoxicity during MASH. We identified Osbpl8 as a vital component of M2-BMDMs by LC-MS/MS analysis and found that Osbpl8 remodels lipid metabolism by inhibiting excessive IRE1α-XBP1-related ER stress. Furthermore, Osbpl8-enriched M2-BMDM-EVs promoted anti-inflammatory and antilipotoxic effects and could be a novel therapeutic target for the clinical treatment of MASH.</p><p><strong>Conclusions: </strong>Our findings indicate that Osbpl8 derived from EVs secreted by anti-inflammatory BMDMs plays important roles in intercellular communication between macrophages and hepatocytes, revealing a novel regulatory mechanism of macrophage homoeostasis in MASH.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"213"},"PeriodicalIF":6.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting casein kinase 2 and ubiquitin-specific protease 7 to modulate RUNX2-mediated osteogenesis in chronic kidney disease.","authors":"Haifeng Lan, Xiao-Jun Yu, Guangsheng Ling, Yuwei Zeng, Yixi Yang, Meiyang He, Yixiao Yu, Ming Shao","doi":"10.1186/s10020-025-01222-5","DOIUrl":"10.1186/s10020-025-01222-5","url":null,"abstract":"<p><strong>Objective: </strong>Chronic Kidney Disease (CKD) frequently leads to Mineral Bone Disorder (MBD), which significantly affects patient quality of life due to bone fragility and metabolic disturbances. This study investigates the role of Casein Kinase 2 (CK2) and Ubiquitin-Specific Protease 7 (USP7) in modulating Runt-related Transcription Factor 2 (RUNX2)-driven osteogenesis in a CKD-MBD mouse model.</p><p><strong>Methods: </strong>A CKD-MBD mouse model was established using 5/6 nephrectomy. Bioinformatic analysis of CKD-related datasets identified RUNX2 and USP7 as key genes implicated in bone metabolism. In vivo and in vitro experiments were conducted to assess the effects of CK2-mediated phosphorylation and USP7-induced deubiquitination on RUNX2 stability and function. Histomorphometry, Enzyme-Linked Immunosorbent Assay (ELISA), and micro-CT analyses were performed to evaluate bone density, strength, and metabolic markers.</p><p><strong>Results: </strong>RUNX2 and USP7 were significantly downregulated in CKD-MBD mice. Silencing RUNX2 impaired osteoblast differentiation, reduced bone density, and increased bone turnover, while CK2 overexpression restored RUNX2 activity by phosphorylation, recruiting USP7 to stabilize RUNX2. Enhanced osteoblast differentiation and improved bone metabolism were observed in CKD-MBD mice upon CK2 activation.</p><p><strong>Conclusion: </strong>CK2 activation promotes RUNX2 phosphorylation and stabilization by USP7, leading to improved osteogenesis and bone metabolism in CKD-MBD. Targeting the CK2/USP7/RUNX2 axis presents a potential therapeutic strategy for managing CKD-related bone disorders.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"214"},"PeriodicalIF":6.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the MEK1-CHK2 axis in macrophages by Staphylococcus aureus promotes mitophagy, resulting in a reduction in bactericidal efficacy.","authors":"Xiaohu Wu, Xin Guan, Chubin Cheng, Zhantao Deng, Zeng Li, Yuanchen Ma, Yanjie Xie, Qiujian Zheng","doi":"10.1186/s10020-025-01274-7","DOIUrl":"10.1186/s10020-025-01274-7","url":null,"abstract":"<p><strong>Background: </strong>Macrophages, which serve as the frontline defenders against microbial invasion, paradoxically become accomplices in Staphylococcus aureus (S. aureus)-driven osteomyelitis pathogenesis through poorly defined immunosuppressive mechanisms.</p><p><strong>Methods: </strong>In this study, we established an S. aureus implant-associated femoral infection model treated with MEK1 inhibitors and evaluated the degree of bone destruction and the bacterial load. We subsequently investigated changes in mitochondrial ROS (mtROS) levels, mitophagy activity, phagocytic-killing ability, and CHEK2 mitochondrial translocation in S. aureus-activated bone marrow-derived macrophages (BMDMs) following MEK1 inhibitor treatment. Finally, in vivo experiments involving different inhibitor combinations were conducted to assess mitophagy levels and the therapeutic potential for treating osteomyelitis.</p><p><strong>Results: </strong>Pharmacological inhibition of MEK1 significantly attenuated bone degradation and the pathogen burden in murine models of osteomyelitis, indicating its therapeutic potential. Investigations using BMDMs revealed that blockade of the MEK1-ERK1/2 axis increases mtROS levels by suppressing mitophagy, directly linking metabolic reprogramming to increased bactericidal activity. Mechanistically, inactivation of the MEK1-ERK1/2 pathway restores CHEK2 expression, facilitating its translocation from the nucleus to mitochondria to restore mtROS levels by inhibiting mitophagy. Importantly, in vivo studies confirmed that the MEK1-ERK1/2-CHEK2 axis is pivotal for controlling mitophagy-dependent bone pathology and bacterial persistence during S. aureus infection.</p><p><strong>Conclusions: </strong>We identified a self-amplifying pathogenic loop in which S. aureus exploits macrophage MEK1 to hyperactivate ERK1/2, leading to the suppression of CHEK2 expression. This process results in excessive mitophagy and decreased mtROS levels, which impair the bactericidal function and enable uncontrolled osteolytic destruction. These findings redefine MEK1 as a metabolic-immune checkpoint and highlight its druggable vulnerability in osteomyelitis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"211"},"PeriodicalIF":6.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Androgens alleviate the depression-like phenotype in female mice by inhibiting AVPR1a in the hippocampal brain region.","authors":"Shimin Ren, Xian Wang, Xueying Huang, Liyang Chen, Bing Zhang, Yang Li, Xin Huang","doi":"10.1186/s10020-025-01272-9","DOIUrl":"10.1186/s10020-025-01272-9","url":null,"abstract":"<p><strong>Background: </strong>The prevalence of depression in women is approximately twice that in men. Differences in androgens levels between men and women, due to gonadal differences, may be associated with the development of depression, although the underlying mechanisms are not well understood.</p><p><strong>Methods: </strong>We evaluated the depressive phenotypes of female mice following low-dose androgen treatment using a variety of behavioral and in vivo electrophysiological experiments. The mRNA profile of hippocampal tissues from female mice treated with dehydroepiandrosterone (DHEA) was constructed through RNA sequencing (RNA-seq). GO and KEGG pathway analyses were performed on the differentially expressed genes. The expression changes of candidate differential genes were verified in hippocampal tissues by quantitative real-time PCR and western blotting. Moreover, the mechanism of action of the DHEA-regulated differential gene (Avpr1a), which is involved in the neuroactive ligand-receptor interaction pathway, was determined in vitro.</p><p><strong>Results: </strong>Chronic DHEA treatment resulted in a distinct antidepressant phenotype and significantly enhanced neuronal excitability of the ventral hippocampal region of female mice. RNA-seq identified the crucial differentially expressed gene, Avpr1a. In vitro experiments showed that DHEA reduced levels of the AVP system. Additionally, ChIP-PCR experiments revealed that Avpr1a directly targets androgen receptor (AR). Cell function experiments demonstrated that DHEA can inhibit AVPR1a expression through AR in a dose-dependent manner, and this effect can be reversed by the androgen receptor antagonist (Flutamide).</p><p><strong>Conclusion: </strong>Androgens (DHEA) exert antidepressant effects by inhibiting the binding of Avpr1a to AR. The Avpr1a gene may serve as a new target for the treatment of depression in women.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"210"},"PeriodicalIF":6.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis.","authors":"Jinjuan Fu, Yuanjuan Tang, Zhen Zhang, Lin Tong, Rongchuan Yue, Lin Cai","doi":"10.1186/s10020-025-01256-9","DOIUrl":"10.1186/s10020-025-01256-9","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"212"},"PeriodicalIF":6.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpression of c-Myc triggers p62 aggregation-mediated mitochondrial mitophagy in cabozantinib resistance of hepatocellular carcinoma.","authors":"Kaibo Yang, Xing Zhang, Kun Yang, Sinan Liu, Jingyao Zhang, Yunong Fu, Tong Liu, Kunjin Wu, Jing Li, Chang Liu, Qichao Huang, Kai Qu","doi":"10.1186/s10020-025-01263-w","DOIUrl":"10.1186/s10020-025-01263-w","url":null,"abstract":"<p><p>Resistance to tyrosine kinase inhibitors (TKIs) poses a significant challenge in the treatment of hepatocellular carcinoma (HCC). Although dysregulation of mitochondrial dynamics has been implicated in the aggressive behaviors of various tumors, the specific role and underlying mechanisms by which this dysregulation contributes to cabozantinib resistance in HCC cells remains insufficiently characterized. By investigating mitochondrial dynamics as central regulators of cabozantinib resistance, this work specifically aims to discover actionable targets for restoring drug sensitivity in treatment-refractory HCC cells. We employed transmission electron microscopy (TEM) and confocal microscopy to analyze mitochondrial morphology in HCC cells resistant to TKIs. Additionally, we utilized an oncogene hydrodynamic injection-induced primary liver cancer mouse model to assess the therapeutic efficacy of combining cabozantinib with other pharmacological agents. Our results demonstrated significant increases in mitochondrial fragmentation, p62 aggregation, and mitophagy in cabozantinib-resistant HCC cells, which correlated with overexpression of c-Myc. Notably, inhibiting mitochondrial fission, p62 aggregation, or autophagy effectively reversed the resistance of HCC cells to cabozantinib. Mechanistically, cabozantinib treatment was shown to induce c-Myc expression, which significantly enhanced mitochondrial fragmentation and p62 aggregation, thereby promoting mitophagy. This mitophagic process selectively eliminated damaged mitochondria, reducing cytochrome C-induced apoptosis in cabozantinib-resistant cells. Ultimately, combining cabozantinib with either the autophagy inhibitor chloroquine or the p62 aggregation inhibitor XRK3F2 resulted in improved anticancer efficacy. In conclusion, c-Myc overexpression facilitates p62 aggregation-mediated mitophagy, leading to cabozantinib resistance in HCC cells. Inhibition of autophagy effectively restores cabozantinib sensitivity in HCC.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"209"},"PeriodicalIF":6.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic heterogeneity in patients with enlarged vestibular aqueduct and Pendred syndrome.","authors":"Marek Sklenar, Silvia Borecka, Lukas Varga, Emanuele Bernardinelli, Juraj Stanik, Martina Skopkova, Miroslav Sabo, Diana Ugorova, Silvia Dossena, Daniela Gasperikova","doi":"10.1186/s10020-025-01262-x","DOIUrl":"10.1186/s10020-025-01262-x","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in the SLC26A4 gene, encoding for Cl^-/HCO₃^- and I^- anion transporter pendrin, are associated with non-syndromic hearing loss with enlarged vestibular aqueduct (NSEVA) and Pendred syndrome (PDS). In the Caucasian population, up to 75% of patients fail to identify a genetic cause through biallelic mutations in the SLC26A4 gene. The CEVA haplotype could therefore play an important role in the diagnostics of NSEVA. The aim of the study was to determine the genetic etiology of hearing loss with EVA or with fully developed PDS in 37 probands and the functional characterization of novel variants identified in the SLC26A4 gene.</p><p><strong>Methods: </strong>To determine the genetic etiology, Sanger sequencing, WES and KASP genotyping assay were used. Functional characterization of SLC26A4 variants c.140G>A (p.R47Q), c.415G>A (p.G139R), c.441G>A (p.M147I), c.481T>A (p.F161I), c.1589A>C (p.Y530S) and c.2260del (p.D754Ifs*5) involved determination of iodide influx, total and plasma membrane pendrin expression level and subcellular localization of pendrin by confocal imaging. The nanopore sequencing of nasopharyngeal swab samples was performed to confirm the pathogenic effect of potential splice site variant c.415G>A.</p><p><strong>Results: </strong>Biallelic variants in the SLC26A4 gene (M2 genotype) were identified in ten probands and a complete CEVA haplotype was confirmed in three probands harbouring SLC26A4 monoallelic variants (M1 genotype). Fifteen variants in the SLC26A4 gene were identified in total, three of which are novel. The functional characterization of the novel variants and variants which were not yet functionally characterized confirmed the pathogenic potential of five out of six tested variants (p.G139R, p.M147I, p.Y530S, p.D754Ifs*5, and p.F161I). Analysis of nasopharyngeal swab samples confirmed exon 4 skipping due to novel variant SLC26A4:c.415G>A. Probands with biallelic SLC26A4 variants had significantly larger thyroid volume per m² of body surface area than subjects with monoallelic SLC26A4 variants and the CEVA haplotype.</p><p><strong>Conclusions: </strong>The genetic aetiology was determined in 13 out of 37 probands (35%), seven manifested with PDS and six with NSEVA. The present study highlights the importance of functional testing to confirm the pathogenicity of SLC26A4 variants and the phenotype-genotype correlation in SLC26A4-related disorders.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"208"},"PeriodicalIF":6.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}