Classical homocystinuria (HCU) is an autosomal recessive disorder caused by pathogenic variants in the cystathionine β-synthase (CBS) gene. Data on the clinical and molecular spectrum of CBS deficiency in Iranian patients and a comprehensive review of the HCU literature remain limited. This study aimed to evaluate the phenotypic and genotypic features of Iranian patients with CBS deficiency and to conduct a comprehensive literature review to investigate the molecular and clinical spectrum. We clinically and genetically characterized ten affected individuals from ten Iranian consanguineous families and combined these data with 2,654 previously published cases (a total of 2,664). Molecular analysis identified ten distinct missense variants, including eight previously reported variants (p.Gly153Arg, p.Gly116Arg, p.Gly259Ser, p.Thr191Met, p.Gly307Ser, p.Thr353Met, p.Asp444Tyr, p.Asn228Ser), and two novel variants (p.Ala452Val and p.Ile311Asn). Our literature review identified a total of 228 variants in CBS, with the central pyridoxal 5’-phosphate (PLP)-binding catalytic domain harbouring over 70
Gestational diabetes mellitus (GDM) increases risk of adverse maternal and fetal outcomes. Using Genome-wide Beadchip arrays, we previously reported differential methylation of 1046 CpG sites in women with GDM. This study aimed to validate three candidate CpG sites in an independent cohort of South African women with and without GDM. DNA methylation was assessed in maternal peripheral blood collected at < 28 weeks of gestation, at three top-most significant CpG sites within Calmodulin Binding Transcription Activator 1 (CAMTA1), Kelch domain-containing protein 3/ Male-Enhanced Antigen 1 (KLHDC3/MEA1), and Collectin Subfamily member 10 (COLECT10), using bisulfite pyrosequencing, in a technical validation group (12 GDM and 12 non-GDM), and an independent biological validation group (46 GDM and 135 non-GDM). Associations between differentially methylated CpGs and maternal clinical characteristics were assessed. Technical validation confirmed decreased methylation at cg23643951 (CAMTA1; -1.53-fold; p = 0.04) and cg21910650 (KLHDC3/MEA1; -1.57-fold; p = 0.004), and increased methylation at cg16306629 (COLECT10; 4.5-fold; p = 0.003) in women with GDM, consistent with the original array findings. No significant differences were observed in the biological validation group. Within the technical validation group, cg21910650 methylation was inversely correlated with fasting glucose (rho=-0.625; p = 0.015) and 1 h OGTT (rho=-0.555; p = 0.034), while cg16306629 was positively correlated with fasting glucose (rho = 0.709; p = 0.006). Technical validation confirmed differential methylation at three CpG sites, though these findings were not reproduced in the larger biological validation group, highlighting the need for validation in independent cohorts. Associations between CpG methylation with glucose concentrations suggest a potential association with glucose regulation during pregnancy, providing a foundation for future validation of these CpG sites as biomarkers for GDM.
Long non-coding RNAs (lncRNAs) are nominated as candidate disease regulators from steady-state RNA-seq differential-expression (DE) catalogs, and short-lived lncRNAs have been proposed to be systematically missed because rapid decay lowers steady-state abundance. We asked how much of that bias it can account for, using 18 half-life strata drawn from 16 metabolic-labeling datasets across 13 human cell lines and 17 uniformly processed disease cohorts (16 TCGA tumor-versus-normal contrasts, one non-alcoholic fatty liver cohort; recount3), matching the half-life cell line to the tumor tissue where possible. Under the pre-filter used here the abundance floor leaves only 24
Alternative splicing of MAPT exon 10 generates 4R- and 3R-Tau isoforms, and its dysregulation is associated with tauopathies including Alzheimer’s disease (AD), for which effective treatments remain lacking. Here, we identify HuR as a novel repressor of MAPT exon 10 alternative splicing. Mechanistically, the RRM1 domain of HuR is critical for mediating its splicing inhibitory effect. HuR binds to the U-rich region downstream of intron 9 in MAPT together with FUBP1, KHSRP, hnRNPD, hnRNPAB, hnRNPDL, and TIAL1. The expression of HuR shows a negative association with that of FUBP1, KHSRP, hnRNPD, and TIAL1. Finally, we demonstrate that HuR regulates the expression and alternative splicing of genes involved in autophagy and apoptosis, pathways dysregulated in AD. Collectively, these findings establish HuR as a regulator of AD-relevant transcriptomic networks and provide a mechanistic basis for exploring HuR-targeted strategies in AD.
Inducing cuproptosis is considered a novel strategy to impede non-small cell lung cancer (NSCLC) progression. ATOX1 suppressed cuproptosis by chelating free copper ions. This study seeks to elucidate the pathways that regulate ATOX1 upstream and thereby pinpoint molecular targets for activating cuproptosis in NSCLC. Cuproptosis was induced with ES-Cu. Malignant phenotypes were assessed using CCK-8, clonogenic, and Transwell assays. RNA immunoprecipitation, RNA pull-down, and actinomycin D chase were used to examine IGF2BP2-ATOX1 mRNA interaction and mRNA stability. Protein-protein interactions and ubiquitination were examined by co-immunoprecipitation. The co-localization of USP11 and IGF2BP2 was visualized by immunofluorescence. IGF2BP2 protein stability was assessed following cycloheximide treatment. Copper content was quantified using a commercial kit. Gene and protein levels were evaluated by RT-qPCR and Western blot. RNA-binding domain mutant rescue experiments were conducted to determine the functional requirement of IGF2BP2 KH domains. A subcutaneous xenograft model was established to validate the regulatory axis in vivo. ATOX1 suppressed cuproptosis to support NSCLC proliferation. IGF2BP2 bound to the CDS of ATOX1 mRNA via the m6A site at position 261, thereby enhancing ATOX1 mRNA stability. The KH3-4 domains of IGF2BP2 were indispensable for this regulation. Upregulation of ATOX1 by IGF2BP2 inhibited cuproptosis and consequently drove NSCLC proliferation. USP11 maintained IGF2BP2 protein stability via deubiquitination, leading to suppression of cuproptosis and promotion of NSCLC progression through the IGF2BP2/ATOX1 axis in vitro. In vivo, the USP11-IGF2BP2-ATOX1 axis might promote NSCLC tumor growth by suppressing cuproptosis. USP11‑dependent deubiquitination stabilized IGF2BP2, which subsequently increased ATOX1 mRNA stability in an m6A‑dependent manner. Elevated ATOX1 expression inhibited cuproptosis and thereby accelerated NSCLC progression.
