Search Results (80)

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by heterogeneous behavioral symptoms and systemic comorbidities, including immune and gastrointestinal dysfunctions. Emerging studies suggest that glycosylation—a fundamental post-translational modification regulating cellular communication and immune responses—may play a role in ASD pathophysiology, yet its contribution remains underexplored. Methods: In this study, we developed an integrative transcriptomic and network analysis framework to investigate glycosylation-related gene expression changes and their functional associations in ASD. Using publicly available datasets from bulk and single-cell RNA sequencing of brain and blood tissues, we focused on four prior-knowledge gene subsets: glycogenes, extracellular matrix glycoproteins, immune response genes, and autism risk genes. Results: Differential expression and pathway enrichment analyses revealed consistent dysregulation of glycosylation pathways, including mucin-type O-glycan biosynthesis, glycosaminoglycan metabolism, GPI-anchor formation, and sialylation, across ASD tissues. These transcriptional changes were functionally linked to altered immune signaling (e.g., IL-17, Toll-like receptor, and complement pathways) and synaptic development pathways, forming a distinct glyco-immune axis. Network analysis identified key glycogenes such as GALNT10, NEU1, LMAN2L, and CHST1 as central molecular nodes, interacting with immune and neuronal regulators. Linkage disequilibrium analysis further revealed ASD-associated SNPs influencing the expression of these glycogenes in both blood and brain tissues. Conclusions: Together, these findings support a model in which disrupted glycosylation contributes to ASD pathophysiology by mediating immune dysregulation and altered neuronal connectivity. This study offers a systems-level framework to understand the molecular complexity of ASD and highlights glycogenes as potential biomarkers and targets for future therapeutic exploration. Full article

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder characterized by hyperphosphatemia and ectopic calcifications. Mutations in GALNT3, which encodes a key enzyme responsible for O-glycosylation of FGF23, represent a major genetic cause of HFTC. This modification is essential for the stability and secretion of FGF23. We investigated a 4-year and 6-month-old Chinese girl with HFTC to characterize the clinical features, identify the causative variants, and explore the underlying pathogenic mechanism. Whole-exome sequencing followed by Sanger validation identified novel compound heterozygous variants in GALNT3 (c.659T>A, p.Ile220Asn and c.1850C>A, p.Ser617*). The patient exhibited hyperphosphatemia with a biochemical profile consistent with FGF23 deficiency, including extremely low intact FGF23 and elevated C-terminal fragments. Functional studies using Western blotting and wheat germ agglutinin affinity chromatography demonstrated that the mutant GALNT3 caused a severe defect in FGF23 O-glycosylation, leading to impaired secretion of intact FGF23. Glycosylated FGF23 was detected only in the medium of cells expressing wild-type GALNT3. These findings indicate that defective O-glycosylation results in failure of FGF23 secretion and functional inactivation. This study expands the mutational spectrum of GALNT3 and provides mechanistic insight into the role of GALNT3 in phosphate homeostasis. Full article

Splenic nodules in dogs that were historically classified under the broad term “fibrohistiocytic nodules” are now recognised as distinct entities within likely a biological continuum. These include lymphoid hyperplasia extending to indolent lymphoma and complex hyperplasia to stromal sarcoma. However, the molecular mechanisms underpinning these proposed progressions remain largely unexplored, particularly at the genomic and transcriptomic levels. This study aimed to delineate and compare the transcriptomic landscapes of four distinct canine splenic nodules through differential gene expression profiling. RNA sequencing was performed on twelve formalin-fixed, paraffin-embedded (FFPE) splenic tissue samples obtained from dogs diagnosed with lymphoid hyperplasia, complex hyperplasia, histiocytic sarcoma, and stromal sarcoma, with normal canine spleen serving as a control tissue. Comparative transcriptomic analysis identified 47 differentially expressed genes (DEGs) between splenic nodules and normal spleen, including CSRP1, SLC40A1, C1QA, C1QC, DLA-12, FTL, FXYD6, MPEG1, OAS3, CSF1, and JMJD6. Furthermore, 39 DEGs were significantly altered among the four splenic lesion types, such as MLC1, ERAS, MOV10L1, LOC102152143, COL4A1, COL4A2, COL12A1, NOTCH3, PLOD2, CPXM2, MRC1, GALNT5, TIMP1, and TFPI2. Many of these genes have previously been implicated in tumorigenesis and metastasis in other malignancies. These findings suggest that dysregulated gene expression may contribute to the activation of stromal cells and macrophages within the spleen, facilitating malignant transformation. Overall, these findings deliver novel transcriptomic insights into canine splenic tumorigenesis that may improve diagnostic precision, inform prognostic assessment, and support the development of targeted therapeutic strategies in veterinary oncology. Full article

Background/Objectives: The polypeptide N-acetylgalactosaminyltransferase (GALNT) family initiates mucin-type O-glycosylation, a post-translational modification that plays a pivotal role in cellular signaling, adhesion, and immune evasion. Dysregulated GALNT expression has been increasingly implicated in carcinogenesis. Methods: We reviewed the literature on the expression, function, and clinical relevance of GALNT isoforms across various cancers, with a focus on their mechanistic roles, biomarker potential, and therapeutic implications. Results: Aberrant GALNT expression is observed in numerous malignancies, including breast, colorectal, gastric, lung, ovarian, and hepatocellular carcinomas. Isoforms such as GALNT1, -T2, -T3, and -T14 contribute to tumorigenesis by modulating the glycosylation of mucins such as Mucin-1 (MUC1), epithelial growth factor receptors (EGFR), and other signaling proteins. These alterations promote cancer cell proliferation, metastasis, epithelial–mesenchymal transition (EMT), and chemoresistance. Deranged GALNT expression is frequently associated with poor prognosis, and certain GALNT genotypes predict treatment response. However, functional redundancy among isoforms poses challenges for selective targeting. Conclusions: Despite their strong potential as modulators of cancer progression, GALNTs face substantial limitations in terms of substrate identification, mechanistic clarity, immune relevance, and therapeutic tractability. Overcoming these challenges requires advanced glycoproteomics, development of isoform-specific tools, and integrated studies across cancer and immunology to fully harness GALNT biology for clinical benefit. Full article

(Background) Retinoblastoma is the most common intraocular malignancy in childhood, primarily caused by mutations in the RB1 gene. However, increasing evidence highlights the significant role of epigenetic mechanisms, particularly DNA methylation and histone acetylation, in tumor initiation and progression. This review aims to summarize and critically assess recent findings on how DNA methylation and histone acetylation contribute to the pathogenesis of retinoblastoma, and to explore their potential role as diagnostic biomarkers and therapeutic targets. (Methods) We searched the databases PubMed, Scopus, and ScienceDirect following PRISMA guidelines. Eligible studies were English-language, open-access articles published within the last ten years, including cohort studies, research articles, and case reports. After rigorous screening, 18 studies were included in the final analysis. (Results) Aberrant DNA methylation was found to inactivate tumor suppressor genes (RB1, RASSF1A, p16INK4A, MGMT) and promote oncogenesis through hypermethylation of regulatory elements. Similarly, histone acetylation’s dysregulation contributed to chromatin remodeling and overexpression of oncogenic factors such as SYK, GALNT8, and lincRNA-ROR. Elevated histone deacetylase (HDAC) activity was also linked to tumor cell proliferation, metastasis, and treatment resistance. Epigenetic inhibitors targeting these pathways demonstrated promising therapeutic potential. (Conclusions) DNA methylation and histone acetylation play a crucial role in the epigenetic regulation of genes implicated in retinoblastoma. Their dysregulation promotes tumorigenesis, and targeting these mechanisms represents a promising avenue for novel diagnostic and therapeutic strategies in pediatric oncology. Full article

Gangliosides are essential for membrane functions, cell recognition, and maintenance of the nervous system. GM2 gangliosidosis is a group of rare genetic lysosomal storage diseases that includes Tay-Sachs disease (TSD), Sandhoff disease (SD), and AB variant. TSD and SD are characterized by deficient β-N-acetyl-hexosaminidase activity. This leads to decreased catabolism of β-N-acetyl-hexosamine-containing ganglioside GM2 in the lysosomes, damage to cells and tissues, and severe neurological symptoms. GM2 is a major ganglioside accumulating in TSD and SD, and is synthesized from GM3 by β1,4-N-acetylgalactosaminyltransferase 1 (B4GALNT1, GM2 synthase). Therapies under development for GM2 gangliosidosis include adeno-associated virus gene therapy, enzyme replacement, and substrate reduction therapy (SRT). The goal of this work was to express and purify human B4GALNT1, characterize its activity, and explore its structural features by protein modeling and substrate docking. We used a panel of synthetic compounds to study their potential inhibition of B4GALNT1 activity. This work can serve to develop SRT for GM2 gangliosidosis. Full article

Social interaction between the domesticated animal and the domesticator is one of the key features of the “domestication syndrome”. Recent research has identified genes in the WBSCR (Williams–Beuren syndrome control region) locus as significant contributors to social behavior in dogs. Large chromosomal deletions and duplications in the human WBSCR locus lead to the development of WBS (Williams–Beuren syndrome) and WBSCR duplication syndrome, respectively. Hypersociability is one of the key symptoms of WBS, while the duplication syndrome is manifested as an autism spectrum disorder (ASD). The data from both humans and dogs highlight the WBSCR locus as one of the key genetic determinants of social behavior in mammals. Several genes in the WBSCR are candidates for the regulation of social behavior in mammals including GTF2I, GTF2IRD, AUTS2 and GALNT17. Here, we discuss the role of WBSCR locus in the regulation of social behavior in mammals including the recent data that highlight the importance of 3D genome alterations in this genomic region for both domestication of animals and development of neurobehavioral disorders in humans. In addition, we bring attention to the role of the poorly characterized GALNT17 gene as a putative player in the development of ASD symptoms and in the regulation of social behavior in animals. We provide a brief summary of its known functions and propose the future research directions aimed at the elucidation of Galnt17 involvement in the regulation of central nervous system (CNS) functions. Full article

High-risk (HR) neuroblastoma (NBL) patients often receive standardized treatment despite wide variations in clinical outcomes, underscoring the need for improved stratification tools. A distinguishing feature of NBL is the patient-specific expression of gangliosides (GGs), particularly GD2, which may serve as biomarkers. We analyzed GG profiles in 18 patient-derived tumors and 11 NBL cell lines using thin-layer chromatography and mass spectrometry. Expression of 0-, a-, and b-series GGs was examined and correlated with clinical risk, outcome, and gene expression data. Low-risk (LR) tumors expressed higher levels of complex b-series GGs. In HR tumors, five GG profiles (A–E) were identified. Profile A featured complex b-series GGs; B showed GD2 dominance; C showed synthesis arrest at GM3 or GD3 due to low expression of the GM2/GD2 synthase, encoded by the B4GALNT1 gene; D included complex a- and b-series GGs; and E was marked by GM2 and GD1a prevalence. B4GALNT1 expression served as a prognostic marker. Relapsed tumors following anti-GD2 therapy typically exhibited reduced GD2 levels, except for one profile A tumor that displayed a ceramide anchor shorter than those found in LR tumors. Astonishingly, the ceramide anchor composition of GD2 itself appears to separate LR and HR NBL, hinting at a role of ceramide synthases in NBL biology. All cell lines expressed GM2, but exhibited very low levels of complex b-series GGs. Profile C was found only in cell lines of the mesenchymal subtype. These findings support further investigation of GG composition and associated enzyme expression as potential biomarkers for risk stratification and treatment response in NBL. Full article

Background/Objectives: Previous multi-ethnic genome-wide association studies (GWAS) have identified the GALNT13 rs10196189 polymorphism as a potential genetic marker linked to sprint–power performance. However, its relevance in East Asian populations, particularly the Han Chinese, remains untested. This study aimed to replicate the association of rs10196189 with elite sprint–power athlete status in Han Chinese males and examine its potential influence on physical performance traits and tissue-specific gene regulation. Methods: A total of 188 healthy Han Chinese males (49 elite sprint–power athletes and 139 non-athletic controls) were genotyped using the TaqMan assay. Assessments included strength, sprint, jump, anaerobic power, DXA-derived body composition, and muscle ultrasound. Logistic regression and ROC analyses evaluated the predictive value of rs10196189. Linear regression models adjusted for age and BMI tested genotype–phenotype associations. Tissue expression and functional networks were analyzed using GTEx and HumanBase databases. Results: The G allele frequency was significantly higher in athletes (12.2%) than in controls (5.4%, p = 0.042). Dominant and additive models effectively predicted athlete status (OR = 2.53–2.58, p < 0.05). Although most traits showed no significant associations post-correction, medial gastrocnemius thickness showed a nominal association (β = 0.371, p = 0.011). Functional analyses revealed high GALNT13 expression in brain tissue and co-expression networks enriched in synaptic signaling and glycosylation pathways. Conclusions: This is the first study to validate the association of GALNT13 rs10196189 with elite athletic status in Han Chinese males. Findings provide novel population-specific evidence and propose tissue-specific glycosylation and neural mechanisms as pathways linking this variant to sprint–power phenotypes. Full article

The intergenic SNP (single-nucleotide polymorphism) rs80860411A>C was identified as a major QTL for drip loss measured on semimembranosus muscle (SM) in pigs. The SNP is located near the GALNT15. The purpose of this study was to analyze the association between rs80860411A>C and fattening, slaughter, and quality traits of Polish pigs. This study was conducted on 235 individuals belonging to two breeds, Polish Large White (n = 187) and Pulawska (n = 48). The rs80860411 genotypes were determined using the PCR-RFLP method. Association analysis was performed for each breed separately. It was shown that rs80860411A>C had a significant effect on fattening performance traits, on several slaughter performance traits, including width of the loin eye and carcass meat content (p ≤ 0.01, p ≤ 0.05), as well as on meat color—redness (a*) (p ≤ 0,05) in Pulawska breed. The obtained results indicate that the studied SNP has the potential to be a QTN and could be included in pig selection programs, especially in Pulawska pigs. Full article

Growth traits are the most important economic traits in red tilapia (Oreochromis spp.) production, and are the main targets for its genetic improvement. Increasing salinity levels in the environment are affecting the growth, development, and molecular processes of aquatic animals. Red tilapia tolerates saline water to some degree. However, few credible genetic markers or potential genes are available for choosing fast-growth traits in salt-tolerant red tilapia. This work used genome-wide association study (GWAS) and RNA-sequencing (RNA-seq) to discover genes related to four growth traits in red tilapia cultured in saline water. Through genotyping, it was determined that 22 chromosomes have 12,776,921 high-quality single-nucleotide polymorphisms (SNPs). One significant SNP and eight suggestive SNPs were obtained, explaining 0.0019% to 0.3873% of phenotypic variance. A significant SNP peak associated with red tilapia growth traits was located on chr7 (chr7-47464467), and plxnb2 was identified as the candidate gene in this region. A total of 501 differentially expressed genes (DEGs) were found in the muscle of fast-growing individuals compared to those of slow-growing ones, according to a transcriptome analysis. Combining the findings of the GWAS and RNA-seq analysis, 11 candidate genes were identified, namely galnt9, esrrg, map7, mtfr2, kcnj8, fhit, dnm1, cald1, plxnb2, nuak1, and bpgm. These genes were involved in ‘other types of O-glycan biosynthesis’, ‘glycine, serine and threonine metabolism’, ‘glycolysis/gluconeogenesis’, ‘mucin-type O-glycan biosynthesis’ and ‘purine metabolism signaling’ pathways. We have developed molecular markers to genetically breed red tilapia that grow quickly in salty water. Our study lays the foundation for the future marker-assisted selection of growth traits in salt-tolerant red tilapia. Full article

Weaning is challenging for dairy calves, frequently resulting in digestive issues. This highlights the importance of implementing appropriate nutritional strategies to enhance gut health and support optimal growth. Postbiotics is a promising alternative to traditional probiotics, conferring health benefits without the risks associated with live bacteria. This study aimed to investigate the effect of dietary supplementation with a postbiotic from dead-cell Limosilactobacillus ingluviei C37 (postbiotic LIC37) on blood biochemical parameters and jejunal epithelium transcriptomic profiles in calves. Fourteen Holstein bull calves were randomly allocated into two groups (n = 7). The control group (CON) received a basic diet, while the postbiotic group (DCLI) was supplemented with 1 g/d of postbiotic LIC37 for 90 days. Blood samples were collected on days 76, 83, and 90, respectively. The jejunal epithelial tissue was obtained from four randomly selected calves per group at day 90 for transcriptome analysis. The results showed that postbiotic LIC37 supplementation reduced globulin, total protein, neutrophil (Neu) levels, and neutrophil-to-lymphocyte ratio (NLR) levels in the DCLI group (p < 0.05). Transcriptomic analysis identified 76 differentially expressed genes (DEGs), with significant upregulation of genes involved in fatty acid metabolism (FABP1), intestinal barrier function (B4GALNT2), and detoxification (GSTA1), alongside downregulation of immune response regulation (FCRLA, FCRL4). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses highlighted enrichment in pathways related to glutathione metabolism, drug metabolism, and vitamin digestion, indicating that postbiotic supplementation improved detoxification, oxidative stress defense, and nutrient absorption in calves. This study provides novel insights into the molecular mechanisms underlying the benefits of postbiotic LIC37 and supports its potential as a sustainable alternative to probiotics in calf nutrition. Full article

Background/Objectives: The aetiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a chronic and severe debilitating disease with a complex phenotype, remains elusive. Associations with infectious diseases and autoimmune and neuropsychiatric disorders have been observed, without the identification of mechanisms. Previous studies suggest that genetic predisposition plays a role, but results are difficult to replicate, with Genome-Wide Association Studies of ME/CFS being challenging due to the relative rareness and heterogeneity of the disorder. Methods: We studied a well-defined Australian patient cohort diagnosed via the International Consensus Criteria, recruited by a specialist ME/CFS clinic. The whole-exome sequences of 77 patients were contrasted against genome variation in the 1000 Genome Project’s genome-matched population. Results: Significant associations with ME/CFS were harboured in genes that belong to the Neuroblastoma Breakpoint Family encoding Olduvai (DUF1220) domains, namely NBPF1 (rs3897177, p-value = 3.15 × 10⁻⁸), NBPF10 (rs1553120233, p-value = 9.262 × 10⁻¹³), and NBPF16 (rs200632836, p-value = 1.04 × 10⁻⁶). Other significantly associated variants were detected in the ATR, RSPH10B, ADGRE5-CD97, and NTRK2 genes, among others. Replication of these results was attempted via a GWAS on raw data from a US cohort, which confirmed shared significant associations with variation identified in the PTPRD, CSMD3, RAPGEF5, DCC, ALDH18A1, GALNT16, UNC79, and NCOA3 genes. Conclusions: These genes are involved in cortical neurogenesis, brain evolution, and neuroblastoma, and have been implicated by several studies in schizophrenia and autism. The sharing of these associations by the two cohorts supports their validity and grants the necessity of future studies to evaluate the implications for ME/CFS aetiology. Full article

The carbohydrate antigen Sd^a is expressed on the cells and secretions of the vast majority of Caucasians. The epitope is formed by a terminal GalNAc residue β4-linked to an α3-sialylated galactose. Different carbohydrate chains N- or O-linked to glycoproteins can be terminated by this epitope. The final step of Sd^a biosynthesis is catalyzed by the GalNAc transferase B4GALNT2. In this review, we discuss the multifaceted aspects of B4GALNT2/Sd^a in fertility and pregnancy, susceptibility to infectious diseases, cancer, chronic kidney diseases, and Duchenne muscular dystrophy. We show how multiple synthetic biology approaches have been adopted to investigate its role. Full article

Background/Objectives: Tumoral calcinosis (TC) is an extremely rare inherited disease characterized by multilobulated, dense ectopic calcified masses, usually in the periarticular soft tissue regions. In a previous study, we isolated a primary cell line from an ectopic lesion of a TC patient carrying a previously undescribed GALNT3 mutation. Here, we researched whether a stem cell (SC) subpopulation, which may play a critical role in TC progression, could be present within these lesions. Methods: A putative SC subpopulation was initially isolated by the sphere assay (marked as TC1-SC line) and characterized for its stem-like phenotype through several cellular and molecular assays, including colony forming unit assay, immunofluorescence staining for mesenchymal SC (MSC) markers, gene expression analyses for embryonic SC (ESC) marker genes, and multidifferentiation capacity. In addition, a preliminary expression pattern of osteogenesis-related pathways miRNAs and genes were assessed in the TC1-SC by quantitative Real-Time PCR (qPCR). Results: These cells were capable of differentiating into both the adipogenic and the osteogenic lineages. Moreover, they showed the presence of the MSC and ESC markers, confirmed respectively by using immunofluorescence and qualitative reverse transcriptase PCR (RT-PCR), and a good rate of clonogenic capacity. Finally, qPCR data revealed a signature of miRNAs (i.e., miR-21, miR-23a-3p, miR-26a, miR-27a-3p, miR-27b-3p, and miR-29b-3p) and osteogenic marker genes (i.e., ALP, RUNX2, COLIA1, OPG, OCN, and CCN2) characteristic for the established TC1-SC line. Conclusions: The establishment of this in vitro cell model system could advance the understanding of mechanisms underlying TC pathogenesis, thereby paving the way for the discovery of new diagnostic and novel gene-targeted therapeutic approaches for TC. Full article