Background Chronic spontaneous urticaria (CSU) is a heterogeneous immune-mediated disorder characterized by recurrent wheals and/or angioedema. Despite advances in understanding its pathogenesis, robust biomarkers for disease stratification remain lacking. MicroRNAs (miRNAs) are key post-transcriptional regulators implicated in immune-mediated diseases and may provide novel insights into CSU. Objective To characterize circulating miRNA expression profiles in CSU and explore their association with clinical phenotypes. Methods Patients were stratified into three groups: urticaria only (n=10), urticaria with angioedema (n=10), and angioedema only (n=10), alongside healthy controls (n=10). Plasma miRNAs were sequenced using the NovaSeq 6000 platform. Data were processed with the nf-core smrnaseq pipeline, followed by multivariate and differential expression analyses in R. Functional enrichment and target prediction analyses were performed using KEGG, Reactome, and WikiPathways. Results Thirty patients (mean age 45.3 years; 76.7% female) were included. Overall, 61 miRNAs were differentially expressed (p < 0.05) across groups, including controls. No miRNAs remained significant after multiple testing correction in pairwise comparisons between clinical subgroups. However, several miRNAs (miR-204-5p, miR-3158-3p, miR-4732-3p, miR-576-5p, and miR-877-5p) showed nominal associations with disease phenotypes. miR-204-5p demonstrated a trend toward reduced expression in patients with urticaria and angioedema (adjusted p = 0.05). Conclusion Circulating miRNA profiles may reflect biological heterogeneity in CSU. Although no subgroup-specific signatures were confirmed after correction for multiple testing, several candidate miRNAs were identified, supporting further investigation of miRNA-based biomarkers in CSU.
Lāsma Lapiņa, Katrīna Daila Neiburga-Vīgante, L. Gailīte et al.· Frontiers in Immunology· 0 citations
Endolysosomal abnormalities are particularly detrimental to the nervous system and have been implicated in neuropsychiatric disorders. Key regulators of the lysosomal and endosomal luminal ion homeostasis are CLC chloride/proton exchangers. We report 15 individuals carrying variants in CLCN3, encoding a ubiquitous endosomal 2Cl−/H+ exchanger, and provide updated clinical information for 5 previously reported individuals. Subjects displayed a broad spectrum of neuropsychiatric symptoms, including developmental delay, intellectual disability, and epilepsy. To reveal the pathogenic mechanism, we investigated ClC-3 variants-mediated ion transport and its regulation by the recently discovered inhibitory beta subunit TMEM9. 12/20 missense variants exhibited altered properties and fell into two classes: those affecting the region binding inhibitory TMEM9 carboxy-termini, and those that broaden the voltage range over which ClC-3 conducts ions. Surprisingly, the latter variants also attenuated TMEM9-mediated inhibition. Both classes produced a toxic gain-of-function, as evident from endolysosomal vacuolization by mutant ClC-3/TMEM9 overexpression. Our results expand the genetic and clinical spectrum of CLCN3-related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9. Loss- and gain-of-function variants of the endosomal chloride/proton exchanger ClC-3 are associated with neurodevelopmental disorders. Identification and characterization of novel variants expands the clinical spectrum of CLCN3 disease and provides detailed insights into pathogenic mechanisms. Most heterozygous missense variants result in a gain of function when studied in co-expression with TMEM9 β-subunits. Several variants affect ClC-3 residues close to the binding pocket of the TMEM9 carboxy-terminus that directly blocks the chloride pathway, thereby weakening the block. Several other variants, located far from the binding site, affect voltage-dependent gating when studied without TMEM9, thereby enhancing currents at endosomal voltages. These variants also weaken TMEM9-mediated inhibition, revealing a link between gating-associated conformational changes and TMEM9 binding. Most heterozygous missense variants result in a gain of function when studied in co-expression with TMEM9 β-subunits. Several variants affect ClC-3 residues close to the binding pocket of the TMEM9 carboxy-terminus that directly blocks the chloride pathway, thereby weakening the block. Several other variants, located far from the binding site, affect voltage-dependent gating when studied without TMEM9, thereby enhancing currents at endosomal voltages. These variants also weaken TMEM9-mediated inhibition, revealing a link between gating-associated conformational changes and TMEM9 binding. Loss- and gain-of-function variants of the endosomal chloride/proton exchanger ClC-3 are associated with neurodevelopmental disorders. Identification and characterization of novel variants expands the clinical spectrum of CLCN3 disease and provides detailed insights into pathogenic mechanisms.
Maya M. Polovitskaya, T. Tkemaladze, L. Jensen et al.· EMBO Molecular Medicine· 0 citations
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