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Membranous nephropathy (MN) is a leading cause of nephrotic syndrome (NS). Since the identification of anti-phospholipase A2 receptor (anti-PLA2R) antibodies in 2009, the use of laser microdissection and tandem mass spectrometry (LMD/MS) has allowed the discovery of several target antigens in MN. In this retrospective cohort study, adult patients evaluated at the Division of Nephrology at Brotzu Hospital (Cagliari, Italy) with biopsy-proven MN and a negative serological test for anti-PLA2R antibody underwent LMD/MS, performed at the Department of Laboratory Medicine and Pathology of Mayo Clinic (Rochester, MN, USA). Twenty-four cases of biopsy-proven MN were available for antigen detection by LMD/MS studies. High total spectral counts of PLA2R were detected in 12 out of 24 (50%) cases. In addition, high spectral counts of THSD7A and NELL1 were detected in two cases each, and EXT1/EXT2 and NCAM1 in one case each. Five putative antigens have been detected: SULF1, PGLYRP, HYAL1, THBS and SEZ6L2. Our study highlights at least two interesting considerations. First, the determination of PLA2R on renal tissue in the diagnosis of PLA2R-associated MN is emphasized since 50% of our cases were falsely diagnosed with PLA2R-negative MN based on the serum anti-PLA2R antibodies determination. Second, our study shows six patients with MN likely associated with putative antigens, two of them showing new antigens never described before in literature (HYAL1 and THBS1). This high prevalence of putative antigens in our cohort is not easily explainable and paves the way for evaluating specific factors in the Sardinian population that could explain this evidence. Show less

Postnatal respiration requires bulk formation of alveoli that produces extensive surface area for gas diffusion from epithelium to the circulatory system. Alveolar morphogenesis initiates at late gestation or postnatal stage during mammalian development and is mediated by coordination among multiple cell types. Here we show that fibroblast-derived Heparan Sulfate Glycosaminoglycan (HS-GAG) is essential for maintaining a niche that supports alveolar formation by modulating both biophysical and biochemical cues. Gli1-CreER mediated deletion of HS synthase gene Ext1 in lung fibroblasts results in enlarged and simplified alveolar structures. Ablation of HS results in loss of a subset of PDGFRα Show less

This study aims to investigate the spectrum and prognosis of membranous nephropathy (MN) in patients with Sjögren's syndrome (SS). SS patients with biopsy-proven kidney involvement who were diagnosed at our center between April 2007 and February 2024 were retrospectively reviewed and analyzed. A total of 290 SS patients with kidney involvement were enrolled. The frequency of MN increased from 16.28% during the 2007-2010 period to 44.05% during the 2021-2024 period. After 2016, MN became the most common renal pathologic type, surpassing tubulointerstitial nephritis. PLA2R antibody or antigen was detected in 74 SS-MN patients, in whom 37 (50%) showed a negative result. Within the PLA2R-negative group, five out of 15 showed positivity for EXT1/EXT2 antigen and one out of eight for THSD7A antigen. Sixty-one SS patients with MN were followed up for >6 months, and 44 (72.13%) of them achieved renal complete remission (CR). Compared with PLA2R-negative patients, PLA2R-positive patients spent a longer time to achieve CR (1.46 ± 1.16 vs. 0.74 ± 0.47 years, MN has become the predominant renal pathologic type in SS. PLA2R-positivity testing followed by EXT1/EXT2 and THSD7A testing is recommended for SS-MN patients. Although most patients can achieve renal CR, the prognosis is usually poor in PLA2R-positive SS-MN patients. Show less

Uterine corpus endometrial carcinoma (UCEC) is one of the most common gynecologic tumors. Due to the high recurrence and metastasis of UCEC, it is crucial for patients to find new biomarkers for diagnosis and therapy. In this study, R software and the TCGA database were used to screen candidate UCEC predictive markers. Western blot and RT-qPCR were performed to detect protein and mRNA expression of EXT1 in UCEC cell lines. In addition, MTT assay, flow cytometry, transwell assay, and wound healing assay were conducted to assess the cell viability, apoptosis, invasion, and migration in UCEC cells. Overlap-extension PCR technique was employed to construct the vector targeting the deletion of the methylated segment of EXT1. The results showed that a total of 11 candidate genes were obtained and EXT1 was identified as a potential target. The expression and methylation levels of EXT1 were both increased in UCEC tissues and cell lines, as well as elevated EXT1 was closely related to the poor prognosis of patients. Besides, the knockdown of EXT1 significantly inhibited the malignant biological behaviors in UCEC cells. Additionally, the current study also found that the deletion of 1559-2146 bp CpG island segment upregulated EXT1 expression and promoted malignant biological behaviors in UCEC cells. Furthermore, the presence of m7G RNA methylation in UCEC cells also was found. In conclusion, the methylation of EXT1 influenced the gene expression, thereby affecting the malignant biological behaviors in UCEC cells and regulating the pathological progression of UCEC. Show less

Men, despite having a lower likelihood of longevity compared to women, generally exhibit better health status when they achieve longevity. The role of DNA methylation in this paradox remains unclear. We performed whole-genome bisulfite sequencing on long-lived men (LLMs), long-lived women (LLWs), younger men (YMs) and younger women (YWs) to explore specific methylation characteristics in LLMs. Despite an accelerated methylation aging rate in LLMs compared to LLWs, we identify thousands of differentially methylated genomic units (DMUs) in LLMs independent of age and sex. These DMUs, validated by an elastic net classifier, can serve as methylation markers for discriminating longevity potential in men. Many are located near health-related genes. Genes like PIWIL1 and EXT1, with promoters featuring DMUs, exemplify the potential role of LLM-specific methylation patterns in suppressing age-related diseases by regulating gene transcription. Our findings provide evidence of a distinct methylation feature contributing to healthy aging and longevity of LLMs. Show less

Autoimmunity towards podocyte antigens causes membranous nephropathy (MN). Numerous MN target antigens (MNTAgs) have been reported, including PLA2R1, THSD7A, NTNG1, TGFBR3, HTRA1, NDNF, SEMA3B, FAT1, EXT1, CNTN1, NELL1, PCDH7, EXT2, PCSK6, and NCAM1, but their podocyte expression has not been thoroughly studied. We screened CZ CELLxGene single-cell RNA (scRNA) sequence datasets for those of adult, fetal, and mouse kidneys and analyzed the above MNTAgs' expression. In adult kidneys, most MNTAgs are present in podocytes, except PCSK6 and NCAM1. PLA2R1 is expressed significantly more than other MNTAgs in podocytes and is a major podocyte marker, consistent with PLA2R1 as the dominant MNTAg. Additionally, PLA2R1 is a top-upregulated gene in the podocytes of chronic kidney disease, acute kidney injury, and diabetic nephropathy, indicating its general role in causing podocyte injury. PLA2R1, NTNG1, HTRA1, and NDNF display podocyte-enriched expression along with elevated chromatin accessibility in podocytes, suggesting transcription initiation contributing to their preference expression in podocytes. In the fetal kidney, most MNTAgs are expressed in podocytes. While PLA2R1 is weakly present in podocytes, SEMA3B is abundantly expressed in immature and mature podocytes, supporting SEMA3B as a childhood MNTAg. In mouse kidneys, Thsd7a is the only MNTAg with a prominent level and podocyte-specific expression. Show less

SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our genome-wide siRNA library screen. We found that defective IAV replication in SLC35B4-deficient A549 cells was independent of virus strain specificity, and the virulence of IAV in Slc35b4 knockdown mice was also decreased. By examining the individual stages of the IAV replication cycle, we discovered that the amount of internalized IAV was significantly reduced in SLC35B4-knockout A549 cells. Mechanistically, SLC35B4 facilitated IAV replication by transporting UDP-xylose, which attaches to the serine residue of heparan sulfate proteoglycans (HSPGs) in the heparan sulfate (HS) biosynthesis pathway. Knockdown of associated host factors (i.e., XYLT2, B4GALT7, EXT1, and EXT2) in the HS biosynthesis pathway also impaired IAV replication. Furthermore, we revealed that AGRN, a unique HSPG family member, was important for the endocytosis of IAV in A549 cells. Moreover, we found that the homeostasis of the AGRN protein was regulated by HS modification mediated by the initial UDP-xylose transporter SLC35B4, thereby affecting the expression level of endocytic adapter AP2B1 to influence IAV internalization. Collectively, these findings establish that SLC35B4 is an important regulator of IAV replication and uncover the underlying mechanisms by which SLC35B4 employs UDP-xylose transport activity to promote IAV internalization.IMPORTANCEThe entry process of IAV represents a favorable target for drug development. In this study, we identified SLC35B4 as an important host factor for the efficient replication of different subtypes of IAV Show less

Hereditary multiple osteochondromas (HMO) is a genetic skeletal disorder caused by defects in exostosin glycosyltransferase 1 (EXT1) or 2 (EXT2) genes. It develops mainly in the growth period and causes multiple osteochondromas (OC) in the physis of the long bones, leading to discomfort and deformities. This study aimed to investigate the anatomical distribution of OC, the frequency of deformities of the lower limbs, scoliosis and surgeries performed in a cohort of patients with HMO at the time of their enrolment in a regional surveillance programme. The study population included HMO patients from the Centre of Heritable and Complex Diseases (CAKS) in the Region of Southern Denmark. Information on surgical procedures and age at the time of diagnosis was obtained from medical records, while deformities were evaluated on early-onset scoliosis (EOS) scans from time of enrolment in the CAKS. A total of 54 patients were included and 44 patients (82%) had an EOS scan. All except one (98%) HMO patient had OC in the knees at the time of their EOS scan. A total of 12 patients (27%) had leg length discrepancy, 30 (68%) had genu varum or valgum and 13 (30%) had scoliosis. The HMO patients had undergone a median of 2.0 (0-14) surgeries, where a median of four (1-23) OC were removed, mostly in the lower limb (68%). The majority of HMO patients in this cohort suffered from major anatomical burdens, leading to multiple surgeries and deformities. We suggest that a programme, such as the CAKS surveillance programme, may be beneficial to screening and follow-up of OC and deformities in patients with HMO. None. Not relevant. Show less

Pure membranous lupus nephritis (pMLN, ISN/RPS-class V) is a rare form of lupus nephritis (LN). Despite being associated with significant comorbidities, it has traditionally been considered a less aggressive subtype. Emerging data challenges this perception, highlighting its potential for chronic kidney disease progression and kidney failure. pMLN is pathologically defined by subepithelial immune-complex deposits and typically presents with nephrotic syndrome, preserved renal function, and fewer systemic/immunologic manifestations compared to proliferative LN (ISN/RPS-classes III/IV). Repeat biopsies reveal frequent histological class switching from pMLN to proliferative and mixed LN forms, underscoring the dynamic nature of the disease and the limitations of clinical markers in reflecting histological activity. While the ISN/RPS kidney biopsy classification provides important prognostic insight, it does not fully capture underlying molecular heterogeneity. Recent advances in precision medicine, including proteomic and biomarker studies (e.g., EXT1/2, NCAM1), offer promising tools for patient stratification and tailored treatments. International guidelines now recommend immunosuppressive therapy for pMLN, aligning treatment strategies more closely with those for proliferative and mixed LN. Overall, pMLN should be considered a distinct but clinically relevant LN subtype requiring personalized management based on clinical, histological and molecular features. Long-term monitoring is essential, as baseline presentation does not reliably predict treatment response or disease trajectory. Show less

Hereditary Multiple Exostoses (HME) is a rare autosomal dominant skeletal disorder resulting from loss-of-function variants in the We aimed to comprehensively review the literature for reported cases of non-skeletal malignancies in individuals with HME and evaluate a potential association with hematologic cancers, particularly in the pediatric population. An extensive literature search was conducted in the PubMed database up to August 2025 using search terms related to HME and malignancy. Eligible reports included case descriptions of non-skeletal cancers occurring in patients with confirmed or suspected HME. Extracted data included patient age, sex, cancer type, and available genetic or molecular findings. Thirteen cases of non-skeletal malignancies associated with HME were identified. Fewer than half underwent molecular genetic testing. Six cases occurred in pediatric patients, four of which involved hematologic malignancies, three leukemias and one Burkitt lymphoma. In adults, malignancies affected a range of organ systems, including respiratory, gastrointestinal, nervous, and endocrine. A marked male predominance was observed (11 males vs. 2 females). Although a definitive causal relationship cannot be established, hematologic malignancies in pediatric HME patients appear to be disproportionately represented among reported cases. This finding highlights the need for further investigation through large-scale, population-based studies incorporating both clinical and genetic data. Show less

Brachydactyly type E (BDE) is characterized by variable shortening of metacarpals or metatarsals, often involving phalanges. It may occur as an isolated anomaly or as part of congenital syndromes. With advancements in molecular diagnostic technologies, how genetic testing enhances the precise diagnosis of BDE remains unclear. Our aims were to establish an algorithm for molecular genetic diagnostics in Chinese children with BDE and to explore the phenotype-genotype correlations of Chinese patients with BDE. We reviewed left-hand wrist X-rays from children visiting Children's Hospital of Soochow University (Jun 2021-Dec 2023). From 60,650 films, 135 BDE cases were identified, and their comprehensive phenotypes were collected. Whole-exome sequencing (WES) with copy number variation (CNV) analysis was performed on 60 patients and their parents. Sanger sequencing was used to validate single nucleotide variants (SNV) and indels. Causative variants were found in 19 patients. SNVs and indels affecting 10 genes were identified in 15 patients, and CNVs in four. Through comprehensive evaluation of genotype-phenotype correlations, we propose a diagnostic algorithm for precise molecular diagnosis in Chinese children with BDE. Show less

A chimeric protein of heparanase and Ig-Fc was designed as a novel tool to expand the detection of structurally heterogeneous heparan sulfate (HS) and related glycosaminoglycans. The whole mouse heparanase gene was combined with the gene segment encoding the mouse IgG1 hinge-Fc domain. A point mutation E335A was inserted to disable putative HS degradation activity. Chimeric proteins consisted of the latent form of the enzyme devoid of HS degradation activity. The chimeric proteins bound to heparin, Show less

The pathogenesis of hereditary multiple exostoses is mainly related to genetic variants and often requires surgical resection when it causes clinical symptoms. This case report describes a variant in the We present the case of an 11-year-old boy who developed hereditary multiple exostoses. The patient presented with multiple bone swellings throughout his body and difficulty squatting due to a swelling in his right thigh. Genetic testing showed that the child had a heterozygous variant in the The diagnosis of hereditary multiple exostoses relies on a clinical examination and genetic testing. Surgical resection is indicated for symptomatic cases with functional impairments. To prevent vascular injuries such as femoral artery rupture, meticulous surgical technique is essential, including thorough smoothing of the resected bone surface and a careful intraoperative assessment of the adjacent neurovascular structures. In cases of postoperative bleeding or suspected pseudoaneurysm, prompt imaging and surgical exploration are critical for timely vascular repair. Show less

Hereditary multiple exostoses (HME), an autosomal dominant disorder with an incidence of 1:50,000 to 1:100,000, is characterised by the formation of multiple osteochondromas arising from the metaphyses of long and flat bones. These osteochondromas often present as painless palpable lumps, though some cases are symptomatic due to mechanical compression or bursitis. Diagnosis of HME is typically clinical and radiological. WHO diagnostic criteria include ≥ 2 radiological osteochondromas in the juxta-epiphyseal region of the long bones. Genetic testing is reserved for ambiguous cases. HME is associated with mutations in the EXT-1 (exostosin-1) and EXT-2 (exostosin-2) genes. Imaging techniques, including conventional radiography, CT, MRI, ultrasound, and nuclear medicine, play a crucial role in diagnosing and assessing HME, with each modality offering distinct advantages in visualising the lesions and associated complications. Common complications include skeletal deformities, fractures, bursitis, as well as neural and vascular abnormalities. Notably, there is a 10% risk of malignant transformation into secondary chondrosarcoma in HME patients, compared to only a 1% risk in those with solitary osteochondromas. Malignant transformation should be suspected in patients with new-onset pain or specific imaging features in an osteochondroma, such as growth of de cartilaginous cap. In these cases, an MRI should be performed to assess the cartilage cap thickness. Advances in imaging techniques and genetic understanding have improved the management and prognosis of HME. Follow-up is essential to rule out malignant transformation. This review summarises current knowledge on the clinical presentation, pathogenesis, imaging characteristics, complications, and treatment of HME. CRITICAL RELEVANCE STATEMENT: HME is a disorder characterised by the formation of osteochondromas arising from long and flat bones. Multi-modality imaging characteristics, clinical presentation, complications, and treatment are highlighted to familiarise the readers with this entity and offer optimal patient care. KEY POINTS: HME is characterised by multiple osteochondromas on long and flat bones. Imaging for HME includes radiography, CT, MRI, ultrasound, and nuclear medicine studies. Complications include non-malignant complications, such as bone deformities and malignant transformation. Cartilage-cap measurement with MRI or US is key to exclude malignancy. Follow-up is essential to rule out malignant transformation of the osteochondromas. Show less

An 88-year-old man was referred with peripheral edema, pleural effusion and nephrotic syndrome that had developed 3 months prior. Based on a kidney biopsy, the majority of glomeruli exhibited capillary wall thickening and the slight area of glomeruli exhibited spike formations and bubbly appearances. Fluorescent immunostaining showed global deposition of neural epidermal growth factor-like 1 (NELL-1), immunoglobulin (Ig) G1 and complement (C) 3c within the glomerular capillary wall. Electron microscopy showed the presence of unique subepithelial electron-dense deposits distributed in a ribbon-like manner along more than 75% of glomerular capillary walls. Fluorescent immunostaining showed no positivity for other recently identified antigens associated with membranous nephropathy, including M-type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), and exostosin 1 (EXT1). A comprehensive medical examination for malignant diseases yielded negative results, and there was no discernible change in κ/λ staining. Additionally, serum complement levels were within the normal range. The patient was therefore diagnosed with NELL-1-positive membranous nephropathy and has been refractory to the treatment with prednisolone, cyclosporine (CyA) and rituximab for 10 months. According to previous reports, segmental or incomplete IgG capillary loop staining have been observed in 93.4% of cases of NELL-1-positive membranous nephropathy. Diffuse and global ribbon-like deposits, as observed in this case, are exceedingly rare. Show less

To evaluate a pathological condition on a skeleton from medieval Veneto (Italy). A male skeleton (T97), aged 35-50 years, from the Early Medieval phase of an archaeological site in the Venetian Lagoon, was examined and radiocarbon dated to Cal 954-1052 CE. The skeletal remains were examined by anthropological methods, by radiographic imaging, full skeletal CT scans, and histological examination. A differential diagnosis was conducted following established protocols. A total of 129 osteochondromas were observed. Both types were evident: sessile and pedunculated. Osteochondromas were evident in most bones of the appendicular skeleton; the skull, vertebrae and ribs remained unaffected. Short stature and forearm deformity were also observed. The differential diagnosis identifies these pathological findings as manifestations of an advanced form of multiple osteochondromas (MO). The significance of this diagnosis lies in its ability to shed light on the natural progression of MO, particularly in the absence of modern surgical interventions. Additionally, it highlights the survival and adaptation of an individual with disabilities within a medieval society. To achieve a definitive confirmation of this diagnosis, genetic testing would be essential. The discovery of only one individual with this condition among 181 analyzed in the context prevents further broader conclusions. Genetic Analysis to confirm the diagnosis of MO and investigate potential genetic mutations, such as those in the EXT1 and EXT2 genes. Show less

Here, we identified a type of hypothetical T7SS effector in This alternative strategy facilitates effectors' delivery, even for fragmented substrates, highlighting its importance in ensuring the functionality of T7SS. Show less

The clinicopathologic and molecular features of serrated lesions with dysplasia in inflammatory bowel disease (IBD) remain poorly understood. We examined a total of 2396 patients treated for IBD at the University of Szeged between 2011 and 2023. Among them, 177 (7%) patients were diagnosed with colorectal neoplasia, of which only 11 (6%) had serrated dysplasia (n = 13). Of the 13 lesions, 5 (38%) showed features of sessile serrated lesion (SSL)-like dysplasia; 1 (8%) exhibited characteristics of traditional serrated adenoma (TSA)-like dysplasia; 6 (46%) were classified as serrated dysplasia, not otherwise specified (NOS); and 1 (8%) displayed mixed features of SSL-like and TSA-like dysplasias. At the time of the serrated dysplasia diagnosis, the mean age of the patients was 56 years. Ten (91%) patients had ulcerative colitis, and one (9%) had Crohn's disease. Pancolitis was observed in seven (64%) patients. The mean duration of IBD at the time of the serrated dysplasia diagnosis was 26 years. Most lesions (n = 9; 69%) were found in the left colon, including SSL-like dysplasia (3/5; 60%) and serrated dysplasia NOS (5/6, 83%). Eleven (85%) lesions had a polypoid endoscopic appearance. The mean size of the serrated dysplasia was 0.8 cm. Most lesions (n = 8; 62%) showed low-grade dysplasia. Serrated dysplasia was often associated with conventional (n = 3; 27%) or nonconventional dysplasia (n = 3; 27%). During the follow-up, 5 (45%) of the 11 patients developed colorectal cancer, including 3 patients with serrated dysplasia NOS, 1 with SSL-like dysplasia, and 1 with TSA-like dysplasia. Whole-exome sequencing revealed that the SSL-like dysplasia harbored mutations in Show less

In recent years, there has been an emergence of new antigens discovered in membranous nephropathy (MN). Whether these antigens have impacted the approach to, and management of, MN patients undertaken by nephrologists is still unclear. We conducted a cross-sectional international survey pertaining to 13 antigens recently discovered in MN. The survey was distributed by the National Kidney Foundation, direct emails, and social media. PLA2R, THSD7A, NELL1, and EXT1/2 testing were readily available while the most common response for other antigen testing was 'Not Performed' or 'Unknown'. All respondents had tested for or treated PLA2R-positive MN. Of 79 respondents, only 12.7% had treated THSD7A, 15.2% for NELL1 and 6.3% for EXT1/2 positive MN. For PLA2R, THSD7A, and NELL1, a majority chose rituximab (75.4, 87.5, and 80.0%, respectively) as initial treatment, and would treat with immunosuppression before completing 6 months of conservative therapy. A majority of respondents would routinely or occasionally omit a kidney biopsy in the setting of positive serum anti-PLA2R antibodies, however, 27.5% would rarely do so. There was no clear consensus across respondents regarding the use of anti-PLA2R serum levels in determining remission. Although many new MN antigens have been discovered, there is limited availability of tests identifying these less common antigens. While the survey suggests potential for utilization of an antigen-tailored approach based on identified differences in screening and treatment practices, there remains a lag in the full adoption of this new information. Further progress in accessibility of antigen testing and research into antigen associations will enable a more individualized approach to the management of MN. Show less

Many factors involved in heparan sulfate (HS) biosynthesis and metabolism have been reported to play roles in viral infection. However, the detailed mechanisms are still not fully understood. In this study, we report that exostosin glycosyltransferase 1 (EXT1), the HS polymerase, is a critical regulatory factor for Zika virus (ZIKV) infection. Knocking out EXT1 dramatically restricts ZIKV infection, which is not due to the inhibition of virus entry resulting from HS deficiency, but mediated by the downregulation of autophagy. Induction of autophagy promotes ZIKV infection, and attenuated autophagy is found in distinct EXT1 knockout (EXT1-KO) cell lines. Induction of autophagy by rapamycin can relieve the ZIKV production defect in EXT1-KO cells. While over-expressing EXT1 results in the reduction of ZIKV production by targeting the viral envelope (E) protein and non-structural protein NS3 in a proteasome-dependent degradation manner. The different roles of EXT1 in ZIKV infection are further confirmed by the data that knocking down EXT1 at the early stage of ZIKV infection represses viral infection, whereas the increase of ZIKV infection is observed when knocking down EXT1 at the late stage of viral infection. This study discovers previously unrecognized intricate roles of EXT1 in ZIKV infection. Show less

Neural epidermal growth factor-like protein 1 (NELL-1) and the exostosin 1/2 complex (EXT1/2) are recently identified target antigens in membranous nephropathy (MN), yet their prevalence and clinical features in Chinese populations remain poorly characterized. This study enrolled 197 consecutive patients with biopsy-proven MN, including 186 with idiopathic membranous nephropathy (IMN) and 11 with secondary membranous nephropathy (SMN). Serum levels of NELL-1 and EXT1/2 antigens were detected Show less

Non-syndromic cleft lip with or without cleft palate (ns-CL/P) is one of the most common craniofacial anomalies with a multifactorial etiology. To investigate the contribution of rare variants to disease risk, we performed whole-exome sequencing (WES) in 58 patients with ns-CL/P from a homogeneous Polish population, excluding from analysis 423 previously investigated cleft candidate genes. After stringent filtering, prioritization, and segregation analysis, we identified 31 likely pathogenic (LP) variants across 30 genes, significantly enriched in categories related to developmental processes. Notably, 29% of variants occurred in genes not previously linked to clefting, including Show less

Individuals with bipolar disorder (BD) exhibit a significantly increased risk of cardiovascular disease, yet the specific mechanisms linking heart failure (HF) and BD remain poorly understood. This study aimed to identify common potential diagnostic biomarkers associated with both conditions. Differentially expressed genes (DEGs) were analyzed separately in HF (GSE57338) and BD (GSE5389) datasets. Key module genes for each condition were identified through co-expression network analysis and intersected with DEGs to pinpoint candidate genes. Subsequently, a protein-protein interaction (PPI) network, receiver operating characteristic (ROC) analysis, and expression validation were employed to identify potential diagnostic biomarkers. Gene set enrichment analysis (GSEA) and drug predictions were also conducted. Clinical validation of biomarker expression was performed via quantitative polymerase chain reaction (qPCR). A total of 44 candidate genes were identified as being associated with both HF and BD. Six potential diagnostic biomarkers ( This study preliminarily explored the common molecular mechanisms between HF and BD, and identified 6 potential biomarkers for early detection, providing a solid theoretical basis for future research on HF and BD. Show less

Hereditary multiple osteochondromas (HMO) is an autosomal dominant disorder caused by heterozygous deleterious variants in the EXT1 or EXT2 genes. While the clinical core phenotype is well established and mainly consists of bone deformities, limb length discrepancies, multiple benign bone neoplasms, and increased risk of chondrosarcoma, the association of HMO with malignancies remains undefined. Only two cases have been reported to date. We report a third patient with HMO and leukemia. New research suggests that EXT1 and EXT2 genes may influence leukemogenesis through several mechanisms, including protein-protein interactions with leukemia-associated genes and modulation by specific microRNAs (miRNAs). Dysregulation of heparan sulfate biosynthesis, a pathway involving exostosin proteins, may disrupt the bone marrow microenvironment, impacting hematopoietic cell growth and differentiation. Show less

Heparan sulfate (HS) is an anionic polysaccharide generated by all animal cells, but our understanding of its roles in human pluripotent stem cell (hPSC) self-renewal and differentiation is limited. We derived HS-deficient hPSCs by disrupting the EXT1 glycosyltransferase. These EXT1 Show less

Autism Spectrum Disorder (ASD) is a complex condition with a multifactorial aetiology including both genetic and epigenetic factors. MicroRNAs (miRNAs) play a role in ASD and may influence metabolic pathways. Glycosylation (the glycoconjugate synthesis pathway) is a necessary process for the optimal development of the central nervous system (CNS). Congenital Disorders of Glycosylation (CDGs) (CDGs) are linked to over 180 genes and are predominantly associated with neurodevelopmental disorders (NDDs) including ASD. From a literature search, we considered 64 miRNAs consistently deregulated in ASD patients (ASD-miRNAs). Computational tools, including DIANA-miRPath v3.0 and TarBase v8, were employed to investigate the potential involvement of ASD-miRNAs in glycosylation pathways. A regulatory network constructed through miRNet 2.0 revealed the involvement of these miRNAs in targeting genes linked to glycosylation. Protein functions were further validated through the Human Protein Atlas. A total of twenty-five ASD-miRNAs were identified, including nine miRNAs that were differentially expressed in cells or brain tissue in ASD patients and associated with glycosylation pathways, specifically protein N- and O-glycosylation and glycosaminoglycan biosynthesis (heparan sulfate). A number of CDG genes and/or ASD-risk genes, including Show less

Renal involvement in TAFRO syndrome usually is present as acute kidney injury with oligoproteinuria. Renal pathology is typically characterized by glomerular microangiopathy without immune deposits, and there have been no reports of membranous nephropathy. While idiopathic multicentric Castleman disease (iMCD), which shares a similar pathophysiology with TAFRO syndrome, has documented several cases of membranous nephropathy, the underlying mechanisms remain unclear. We present a case of TAFRO syndrome presenting with nephrotic syndrome, and kidney biopsy revealed exostosin 1/exostosin 2 (EXT1/EXT2)-associated membranous nephropathy. EXT1/EXT2 is considered a potential target antigen in autoimmune membranous nephropathy, suggesting their potential pathogenic role in this case. In iMCD cases with membranous nephropathy, IL-6 levels tend to be slightly low, while VEGF levels are significantly elevated, as seen in the present case. This cytokine profile may contribute to the differences in renal pathological findings and may also be involved in the response to treatment. This case may enhance our understanding of the pathophysiology of membranous nephropathy in TAFRO syndrome and iMCD. Show less

Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be explained by these mutations, and its pathogenic mechanisms are not fully understood. Herein, utilizing whole-exome sequencing and genetic screening with a family trio design, we identify two novel rare mutations co-segregating with HME in a Chinese family, including a nonsense mutation (c.204G>A, p.Trp68*) in EXT1 and a missense mutation (c.893T>G, p.Phe298Cys) in FUT7. Functional assays reveal that the FUT7 mutation affects the cellular localization of FUT7 protein and regulates cell proliferation. Notably, the simultaneous loss of fut7 and ext1 in a zebrafish model results in severe chondrodysplasia, indicating a functional link between FUT7 and EXT1 in chondrocyte regulation. Additionally, we unveil that FUT7 p.Phe298Cys reduces EXT1 expression through IL6/STAT3/SLUG axis at the transcription level and through ubiquitination-related proteasomal degradation at the protein level. Together, our findings not only identify novel germline mutations in FUT7 and EXT1 genes, but also highlight the critical interaction between these genes, suggesting a potential 'second-hit' mechanism over EXT1 mutations in HME pathogenesis. This insight enhances our understanding of the mechanisms underlying HME and opens new avenues for potential therapeutic interventions. Show less

Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disease. Genetic linkage analyses have identified that mutations in the exostosin glycosyltransferase (EXT)1 and EXT2 genes are linked to HME pathogenesis, with EXT1 mutation being the most frequent. The aim of this study was to generate a mice model with Ext1 gene editing to simulate human EXT1 mutation and investigate the genetic pathogenicity of Ext1 through phenotypic analyses. We designed a pair of dual sgRNAs targeting exon 1 of the mice Ext1 gene for precise deletion of a 46 bp DNA fragment, resulting in frameshift mutation of the Ext1 gene. The designed dual sgRNAs and Cas9 proteins were injected into mice zygotes cytoplasm. A total of 14 mice were obtained via embryo transfer, among which two genotypic chimera mice had a deletion of the 46 bp DNA fragment in exon 1 of the Ext1 gene. By hybridization and breeding, we successfully generated heterozygous mice with edited Ext1 gene (Ext Show less