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Results for “Loss of Function Mutation”

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PubMed2026

Loss of Function Dnmt3a Mutation Leads to Aberrant Neutrophil Migration.

Clonal hematopoiesis (CH), an age-related expansion of somatically mutated hematopoietic clones, is associated with increased risk of severe infections including coronavirus disease (COVID)-19, yet the underlying mechanisms remain unclear. Here, we investigated the impact of Dnmt3a deficiency in a murine model of influenza A virus (IAV) pneumonia. Dnmt3a-deficient mice exhibited increased pulmonary viral burden and reduced neutrophil accumulation in IAV-infected lungs despite comparable circulating neutrophil numbers. Functional analyses of neutrophils showed impaired chemotactic migration in vitro, whereas maturation, antimicrobial enzyme content, and metabolic capacity were unchanged. Transcriptomic profiling revealed downregulation of pathways involved in chemotaxis, cytokine signaling, and cellular activation, including reduced expression of Cxcr1. Supporting the translational relevance of these findings, proteomic analysis of plasma from individuals with germline DNMT3A mutations (Tatton-Brown-Rahman syndrome) revealed alterations in proteins associated with cell migration and cytoskeletal dynamics. Collectively, our findings demonstrate that Dnmt3a loss compromises innate immune defense by impairing neutrophil migration in a cell-intrinsic manner, leading to ineffective pathogen clearance. This work provides mechanistic insight into how CH-associated mutations contribute to age-associated susceptibility to infection and highlights altered leukocyte trafficking as a potential therapeutic target in aging populations with CH.

Animals↗

PubMed2024

Proteome-scale prediction of molecular mechanisms underlying dominant genetic diseases.

Many dominant genetic disorders result from protein-altering mutations, acting primarily through dominant-negative (DN), gain-of-function (GOF), and loss-of-function (LOF) mechanisms. Deciphering the mechanisms by which dominant diseases exert their effects is often experimentally challenging and resource intensive, but is essential for developing appropriate therapeutic approaches. Diseases that arise via a LOF mechanism are more amenable to be treated by conventional gene therapy, whereas DN and GOF mechanisms may require gene editing or targeting by small molecules. Moreover, pathogenic missense mutations that act via DN and GOF mechanisms are more difficult to identify than those that act via LOF using nearly all currently available variant effect predictors. Here, we introduce a tripartite statistical model made up of support vector machine binary classifiers trained to predict whether human protein coding genes are likely to be associated with DN, GOF, or LOF molecular disease mechanisms. We test the utility of the predictions by examining biologically and clinically meaningful properties known to be associated with the mechanisms. Our results strongly support that the models are able to generalise on unseen data and offer insight into the functional attributes of proteins associated with different mechanisms. We hope that our predictions will serve as a springboard for researchers studying novel variants and those of uncertain clinical significance, guiding variant interpretation strategies and experimental characterisation. Predictions for the human UniProt reference proteome are available at https://osf.io/z4dcp/.

Humans↗

PubMed2024

Nonlethal deleterious mutation-induced stress accelerates bacterial aging.

Random mutagenesis, including when it leads to loss of gene function, is a key mechanism enabling microorganisms' long-term adaptation to new environments. However, loss-of-function mutations are often deleterious, triggering, in turn, cellular stress and complex homeostatic stress responses, called "allostasis," to promote cell survival. Here, we characterize the differential impacts of 65 nonlethal, deleterious single-gene deletions on Escherichia coli growth in three different growth environments. Further assessments of select mutants, namely, those bearing single adenosine triphosphate (ATP) synthase subunit deletions, reveal that mutants display reorganized transcriptome profiles that reflect both the environment and the specific gene deletion. We also find that ATP synthase α-subunit deleted (ΔatpA) cells exhibit elevated metabolic rates while having slower growth compared to wild-type (wt) E. coli cells. At the single-cell level, compared to wt cells, individual ΔatpA cells display near normal proliferation profiles but enter a postreplicative state earlier and exhibit a distinct senescence phenotype. These results highlight the complex interplay between genomic diversity, adaptation, and stress response and uncover an "aging cost" to individual bacterial cells for maintaining population-level resilience to environmental and genetic stress; they also suggest potential bacteriostatic antibiotic targets and -as select human genetic diseases display highly similar phenotypes, - a bacterial origin of some human diseases.

Escherichia coli↗

PubMed2026

Inference of elevated mutation rates and variant effects using 700k exomes.

Genomic sequencing is now widely accessible for genetic diagnostics and is emerging as a component of newborn screening. This technological development generates the need to characterize incoming mutations, create comprehensive datasets of genes causing rare Mendelian disorders, and identify pathogenic variants. Large-scale exome sequencing datasets such as Genome Aggregation Database (gnomAD) have been assembled to help address these challenges. The recent release of gnomAD (v4; n = 730,947) uncovers millions of rare coding variants, many of which have arisen more than once by independent recurrent mutations in the rapidly growing recent human population. Here, we use newly developed theoretical understanding of sampling properties of rare variants to estimate key population genetics parameters of practical importance to human genetics such as demography history, mutation rate, and selection. Solely relying on population data, our method Population Inferred Estimates of Selection (PIES) identifies novel genes with loss-of-function mutational hotspots likely due to selection in spermatogonia. PIES efficiently estimates selection coefficients for heterozygous loss-of-function variants. Combining population genetics inference with variant effect predictors, PIES predicts pathogenic missense mutations and improves variant prioritization for genetic diagnostics and newborn screening.

Journal Article↗

PubMed2026

Disruption of major Ptchd1 isoforms causes autistic traits in social behavior and communication.

PTCHD1 is an X-linked three-exon gene associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). Mice lacking Ptchd1 exon 2 (Ptchd1Δexon2) exhibit hyperactivity and learning impairments, but do not recapitulate ASD-like traits. Through mapping of clinically reported loss-of-function mutations in human patients, we determined that PTCHD1 exon 3 is a high-risk locus. We therefore generated an alternative Ptchd1 knockout mouse model by targeting Ptchd1 exon 3 (Ptchd1Δexon3) using CRISPR/Cas9. Our analyses revealed that two major PTCHD1/Ptchd1 transcripts-a (full-length) and c (shorter)-were expressed in the brain. In Ptchd1Δexon2 mice, Ptchd1_a was lost, but Ptchd1_c was compensatorily upregulated, and these mice showed no ASD-like social deficits. In Ptchd1Δexon3 mutants, both Ptchd1_a and Ptchd1_c were lost, along with dysregulation of social and communication behaviors, increased repetitive behavior, and motor and learning impairments. Our side-by-side analyses of Ptchd1Δexon2 and Ptchd1Δexon3 mice suggest a functional link between PTCHD1/Ptchd1 and ASD, demonstrating that loss-of-function mutations disrupting C-terminal Ptchd1 lead to robust ASD-relevant phenotypes in mice, more faithfully recapitulating clinically observed traits.

Animals↗

PubMed2025

Quinoxaline-based anti-schistosomal compounds have potent anti-plasmodial activity.

The human pathogens Plasmodium and Schistosoma are each responsible for over 200 million infections annually, especially in low- and middle-income countries. There is a pressing need for new drug targets for these diseases, driven by emergence of drug-resistance in Plasmodium and an overall dearth of drug targets against Schistosoma. Here, we explored the opportunity for pathogen-hopping by evaluating a series of quinoxaline-based anti-schistosomal compounds for their activity against P. falciparum. We identified compounds with low nanomolar potency against 3D7 and multidrug-resistant strains. In vitro resistance selections using wildtype and mutator P. falciparum lines revealed a low propensity for resistance. Only one of the series, compound 22, yielded resistance mutations, including point mutations in a non-essential putative hydrolase pfqrp1, as well as copy number amplification of a phospholipid-translocating ATPase, pfatp2, a potential target. Notably, independently generated CRISPR-edited mutants in pfqrp1 also showed resistance to compound 22 and a related analogue. Moreover, previous lines with pfatp2 copy number variations were similarly less susceptible to challenge with the new compounds. Finally, we examined whether the predicted hydrolase activity of PfQRP1 underlies its mechanism of resistance, showing that both mutation of the putative catalytic triad and a more severe loss of function mutation elicited resistance. Collectively, we describe a compound series with potent activity against two important pathogens and their potential target in P. falciparum.

Quinoxalines↗

PubMed2026

Phase 1 trial and biomarker analysis of Buparlisib with weekly Cisplatin and Radiotherapy in high risk locally advanced squamous cell cancer of the Head and Neck.

PURPOSE: We evaluated the pan-PI3K inhibitor buparlisib with weekly cisplatin and radiotherapy among patients with locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) and tobacco history. PATIENTS AND METHODS: Patients with stage III/IV LA-SCCHN (AJCC7), ≥10 pack-year tobacco use treated with curative intent were enrolled. Patients received buparlisib during a 2-week run-in phase and during standard 70Gy of radiotherapy plus weekly cisplatin. An exploratory analysis of genomic sequencing was performed on biopsy specimens Results: Twenty-three patients were enrolled (n=17 at the MTD (buparlisib 40 mg daily, CDDP 30mg/m2/week)). Ninety-one percent (21/23) had stage IV disease. HPV was detected in 15 of 18 cases with oral/oropharyngeal disease. 5 patients suffered recurrences of whom 3 had activating mutations along the PI3K pathway. In 5 patients whose disease responded during the 2 week run-in phase with buparlisib alone, 3 of 4 with sequencing data showed loss-of-function mutations in either Tumor Necrosis Factor Receptor Associated Factor 3 (TRAF3), and/or Cylindromatosis Lysine Deubiquinatinase (CYLD). Preclinical studies with mutations in TRAF3 or CYLD via CRISPR/Cas9 knockout in HPV+SCCHN cells demonstrate that loss of TRAF3 or CYLD may sensitize SCCHN cell lines to PI3K through mechanisms other than blocking NFκb pathway. CONCLUSIONS: Buparlisib with CRT was feasible and active, though escalation to the standard weekly cisplatin dose of 40 mg/m2 was not possible. Our data suggests that TRAF3/CYLD mutant SCCHN may be susceptible to PI3K inhibition whereas PI3K pathway activation appeared to be associated with poor outcomes in this limited dataset.

Journal Article↗

PubMed2026

Recurrent reversible mutations at gaf1 driving metastable TORC1 inhibitor resistance in fission yeast.

Metastable phenotypic inheritance is often attributed to epigenetic mechanisms, but reversible genetic alterations can produce similar instability. Here, we investigated the basis of unstable resistance to TORC1 inhibitor (rapamycin plus caffeine) in Schizosaccharomyces pombe. Six independent, metastable resistant mutants were isolated. Genetic mapping positioned the causal lesion to a single Mendelian locus, which sequencing identified as gaf1, encoding a GATA transcription factor and a key negative regulator of growth downstream of TORC1. In each mutant, distinct loss-of-function mutations (insertions, deletions, or point mutations) were found in gaf1 in the resistant state, and these mutations precisely reverted to the wild-type sequence upon loss of resistance. Restoring the wild-type gaf1 allele abolished resistance, indicating that reversible genetic disruption of gaf1 is both necessary and sufficient for the metastable phenotype. Furthermore, strong resistance in several strains from a genome-wide deletion library was due to secondary, inactivating mutations in gaf1, underscoring its role as a recurrent adaptive target under rapamycin plus caffeine treatment. Mechanistically, gaf1 inactivation established a distinct basal transcriptome and pronounced derepression of translation and metabolic programs upon drug treatment. While rapamycin plus caffeine triggered extensive chromatin remodeling and H3K9 methylation contributed partially to resistance, these epigenetic changes were most consistent with a downstream modifying layer. Our study shows that metastable drug resistance in fission yeast is predominantly associated with recurrent, reversible genetic inactivation of the central transcriptional regulator gaf1, demonstrating how rapidly reversible genetic switches can drive adaptive evolution.IMPORTANCEDistinguishing between genetic and epigenetic inheritance is fundamental to understanding how cells adapt to environmental stress. In the fission yeast Schizosaccharomyces pombe, rapid and reversible drug resistance is often assumed to be driven by epigenetic switches that change gene activity without altering DNA. However, our study reveals that this instability can be caused by physical mutations in a single gene, gaf1, which acts as a genetic toggle. These mutations appear under drug pressure and precisely revert to the original sequence when the drug is removed. We also demonstrate that these spontaneous mutations can contaminate standard laboratory yeast collections, leading to potential misinterpretation of experimental data. These findings broaden our understanding of unstable inheritance and show that DNA sequences can be far more dynamic than previously recognized during rapid evolution and the development of drug resistance.

TORC1 signaling↗

PubMed2025

Distinct patterns of de novo coding variants contribute to Tourette Syndrome etiology.

Tourette syndrome (TS) is a highly heritable childhood-onset neuropsychiatric disorder characterized by persistent motor and vocal tics. While both common and rare variants contribute to TS susceptibility, the role of rare de novo mutations (DNMs) remains incompletely characterized. Here, we report findings from the largest TS whole-exome sequencing study to date, analyzing 1,466 TS trios alongside 6,714 autism spectrum disorder (ASD) trios and 5,880 unaffected sibling controls from the Simons Simplex Collection (SSC) and SPARK cohorts. Leveraging a trio-based design across these cohorts enabled calibrated assessment of DNM burden while controlling for background mutation rates. We observed a significant exome-wide enrichment of protein-truncating DNMs in TS probands, particularly within genes intolerant to loss-of-function variation (pLI ≥ 0.9), with little contribution from damaging missense variants. Notably, TS probands did not exhibit enrichment in previously implicated ASD or developmental delay (DD) genes, but elsewhere in the genome, suggesting a distinct rare variant architecture. Using a Bayesian statistical framework that integrates both de novo and rare inherited coding variants, we identified three candidate TS risk genes with FDR ≤ 0.05: PPP5C , EXOC1 , and GXYLT1 . Literature shows that they have prior links to neurodevelopmental and psychiatric disorders. These findings reveal a rare variant burden in TS that is genetically distinguishable from ASD, underscore the importance of loss-of-function mutations in TS risk, and nominate novel candidate genes for future functional investigation.

Journal Article↗

PubMed2026

Establishment of a human induced pluripotent stem cell line, KMUGMCi011-A, from a patient bearing a frameshift mutation in the KMT2D gene leading Kabuki syndrome 1.

Kabuki syndrome 1 is a rare genetic disorder typically characterized by facial abnormalities, cognitive impairment, developmental delay and organ dysfunction. It is caused by a loss-of-function mutation in the KMT2D gene. The peripheral blood mononuclear cells from a patient carrying frameshift mutation in the KMT2D gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit. This frameshift mutation results in a truncated protein. This established human induced pluripotent cell line will allow proper in vitro disease modelling of Kabuki syndrome 1.

Journal Article↗

PubMed2026

KEAP1 loss-of-function suppresses immunogenic ferroptosis and limits PD-1 blockade efficacy through an NRF2-FSP1 pathway.

Loss-of-function mutations in Kelch-like ECH-associated protein 1 (KEAP1) frequently occur in lung adenocarcinoma and are associated with poor prognosis and limited benefit from immunotherapy. However, the mechanisms linking KEAP1 deficiency to immune evasion remain elusive. We combined clinical data analysis, in vivo tumor models, and in vitro co-culture systems to investigate how KEAP1 deficiency shapes dendritic cell (DC) biology and response to PD-1 blockade. Ferroptosis induction assays, damage-associated molecular patterns (DAMPs) quantification, cytokine profiling, and mechanistic interrogation of the FSP1-CoQ10 axis were performed to delineate pathways.KEAP1 mutations correlated with poor response to PD-1 blockade and reduced DC infiltration. In mice, KEAP1-deficient tumors exhibited accelerated growth and reduced DC and CD8+ T-cell infiltration, consistent with an immune-cold phenotype. Mechanistically, KEAP1 loss impaired DC function in vitro, as evidenced by reduced maturation, phagocytosis, and naïve CD8+ T-cell priming capacity. This defect was linked to two mechanisms. First, KEAP1-deficient tumor cells resisted ferroptosis and failed to release immunogenic DAMPs, including extracellular ATP, HMGB1, and calreticulin. Second, KEAP1 deficiency reprogrammed the cytokine secretion profile, with downregulation of CCL2, IL-6, CXCL1, and CXCL2, thereby diminishing DC recruitment and inflammatory signaling. Notably, inhibition of the FSP1-CoQ10 antioxidant axis restored ferroptosis-associated immunogenic cell death. Our study identifies KEAP1 deficiency as a driver of immune-cold tumor microenvironments and resistance to PD-1 blockade, acting through impaired ferroptosis-induced immunogenic cell death and disrupted DC function. Genetic FSP1 deletion restored ferroptosis-associated immunogenicity and DC activation in KEAP1-deficient cells, supporting FSP1 as a potential therapeutic target for further in vivo evaluation.

DAMPs↗

PubMed2025

Developing a disease-specific accessible transcriptional signature as a biomarker for ataxia with oculomotor apraxia type 2.

BACKGROUND: Genetic ataxias are clinically heterogenous neurodegenerative conditions often involving rare or private mutations and it is often difficult to assign pathogenicity to rare gene variants solely based on DNA sequencing. An effective functional assay from an easy-to-obtain biospecimen would aid this assessment and be of high clinical value. SETX encodes a ubiquitous DNA/RNA helicase crucial for resolving R-loops and maintaining genome stability. Loss-of-function mutations cause a recessive disorder, Ataxia with Oculomotor Apraxia Type 2 (AOA2). METHODS: Here we utilize Weighted Gene Co-expression Network Analysis (WGCNA) from patient blood to construct an AOA2-specific transcriptomic signature as a biomarker to evaluate SETX variants in patients clinically suspected of having AOA2. RESULTS: WGCNA from peripheral blood RNA of 11 AOA2 patients from 7 families initially identified a single gene module that was modestly effective in distinguishing individuals with AOA2 from controls (sensitivity 73%, specificity 97%) and was able to robustly differentiate AOA2 patients from those with genetically distinct, yet phenotypically similar, neurological disorders (sensitivity 100%, specificity 100%). An independent derivation of the transcriptional biomarker identified a dual module model that was able to better distinguish individuals with AOA2 from controls (sensitivity 100%, specificity 97%). As validation, we examined a second cohort of 21 patients from 13 families and demonstrate that this dual module transcriptional biomarker could discriminate patients clinically suspected of AOA2 from controls (57%, 95%CI: 34%-78%). Overall, the transcriptional biomarker was able to separate AOA2 subjects (n = 32) from controls (n = 35) with 72% sensitivity and 97% specificity. Notably, this transcriptomic biomarker enabled verification of the first pathogenic SETX mutation found in a non-canonical transcript, expanding the spectrum of mutations that contribute to AOA2. CONCLUSIONS: Our study identified a transcriptional biomarker that was able to differentiate AOA2 from controls and from other related neurological disorders, consequently expanding the spectrum of known pathogenic mutations. This proof-of-concept study illustrates that transcriptional biomarkers may be used to validate variants of uncertain significance in known genetic diseases.

Humans↗

PubMed2025

STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency.

Abnormalities in the Wnt pathway are major drivers of cancer. RNF43 loss-of-function mutations are frequently detected in aggressive cancers lacking targeted therapies, underscoring the need to uncover key regulators and targets of this pathway. Using a double death trap (DDT) Wnt reporter and genome-wide CRISPR screen, we identified STT3A as an essential regulator of Wnt signaling. Genetic and pharmacological inhibition of STT3A suppressed aberrant Wnt activity caused by RNF43/ZNRF3 loss. Importantly, suppression of STT3A blocked the growth of RNF43-deficient cancer cell lines, patient-derived organoids, and spontaneous tumors. Mechanistically, STT3A regulates Wnt/β-catenin signaling via LRP6, but not LRP5. Glycosylation of LRP6 by STT3A is required for Wnt ligand binding. Notably, STT3A depletion displayed milder effects on bone homeostasis, as supported by phenotypes in STT3A-deficient patients. Together, this study established STT3A as a critical Wnt regulator through LRP6 glycosylation and a therapeutic target for RNF43-deficient cancers.

Humans↗

PubMed2024

STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1.

Cohesin complexes carrying STAG1 or STAG2 organize the genome into chromatin loops. STAG2 loss-of-function mutations promote metastasis in Ewing sarcoma, a pediatric cancer driven by the fusion transcription factor EWS::FLI1. We integrated transcriptomic data from patients and cellular models to identify a STAG2-dependent gene signature associated with worse prognosis. Subsequent genomic profiling and high-resolution chromatin interaction data from Capture Hi-C indicated that cohesin-STAG2 facilitates communication between EWS::FLI1-bound long GGAA repeats, presumably acting as neoenhancers, and their target promoters. Changes in CTCF-dependent chromatin contacts involving signature genes, unrelated to EWS::FLI1 binding, were also identified. STAG1 is unable to compensate for STAG2 loss and chromatin-bound cohesin is severely decreased, while levels of the processivity factor NIPBL remain unchanged, likely affecting DNA looping dynamics. These results illuminate how STAG2 loss modifies the chromatin interactome of Ewing sarcoma cells and provide a list of potential biomarkers and therapeutic targets.

Sarcoma, Ewing↗

PubMed2025

Impaired hematopoiesis and embryonic lethality at midgestation of mice lacking both lipid transfer proteins VPS13A and VPS13C.

VPS13 is the founding member of a family of proteins that mediate lipid transfer at intracellular membrane contact sites by a bridge-like mechanism. Mammalian genomes comprise 4 VPS13 genes encoding proteins with distinct localizations and function. The gene duplication resulting in VPS13A and VPS13C is the most recent in evolution and, accordingly, these two proteins are the most similar to each other. However, they have distinct subcellular localizations and their loss of function mutations in humans are compatible with life but result in two different age-dependent neurodegenerative diseases, chorea-acanthocytosis and Parkinson's disease, respectively. Thus, it remains unclear whether these two proteins have overlapping functions. Here, we show that while Vps13a KO and Vps13c KO mice are viable, embryonic development of Vps13a/Vps13c double knockout (DKO) mice is arrested at midgestation. Prior to death, DKO embryos were smaller than controls, were anemic and had a smaller liver, most likely reflecting defective embryonic erythropoiesis which at this developmental stage occurs primarily in this organ. Further analyses of erythroid precursor cells showed that their differentiation was impaired and that this defect was accompanied by activation of innate immunity as revealed by upregulation of interferon stimulated genes (ISGs). Additionally, the RIG-I and MDA5 components of dsRNA triggered innate immunity were found upregulated in the DKO fetal liver. Activation of innate immunity may result from loss of integrity of the membranes of intracellular organelles, such as mitochondria and autophagic lysosomes, or to impaired autophagy, due to the absence of these lipid transport proteins. The surprising and striking synthetic effect resulting for the combined loss of VPS13A and VPS13C suggests that despite of the different localization of these two proteins, the lipid fluxes that they mediate are partially redundant.

Animals↗

PubMed2025

CRISPR for cystic fibrosis: Advances and insights from a systematic review.

Cystic fibrosis (CF) is a severe genetic disorder caused by loss-of-function mutations in the CFTR gene. Gene-editing approaches have the potential to correct such mutations. This systematic review outlines the mechanisms of the main CRISPR-based technologies, and, through cross-study comparisons, analyzes 27 research articles that applied them to target CF-causing variants. We report and discuss the strategy design, target cell selection, editing efficiency, prevalence of editing byproducts, and levels of CFTR functional restoration achieved in each work, with the aim of providing technical insights for further exploration of CRISPR-based gene-editing approaches. Our findings show that the F508del and W1282X mutations were the most extensively studied CF-causing variants, though over fifteen mutations were targeted overall. The majority of works under review explored the use of homology-directed repair or base editing, with a growing number of studies reporting efficient prime editing. Some studies tackled multiple individual mutations, compared different editors, or tested strategies across various models, while others focused on approaches that rescue CFTR function without directly correcting a mutation. Several works also proposed strategies that could address multiple variants with a single approach, while others highlighted technical difficulties in editing certain regions of the CFTR gene. This cross-study comparison also emphasizes the need for standardized reporting of editing efficiency and functional recovery, and stresses the importance of further single-cell RNA sequencing and in vivo studies to reach clinically relevant conclusions. As gene-editing techniques continue to evolve, and with over 60 ongoing CRISPR-based clinical trials, there is growing optimism for meaningful advancements in CF gene-editing therapeutics.

Cystic Fibrosis↗

PubMed2026

Targeting CD44 reverses sphingomyelin-induced oligodendrocyte maturation arrest in acid sphingomyelinase deficiency.

Loss-of-function mutations in the smpd1 gene cause acid sphingomyelinase deficiency (ASMD). Early neurodegeneration and lethality characterize its infantile neurovisceral form (type A). While neuronal dysfunction was traditionally considered the primary driver of the pathology, recent evidence suggests that dysmyelination and microgliosis are not merely secondary features. Specifically, myelin debris undermines the protective role of microglia, contributing to neuroinflammation and neuronal death. Herein, we examined central myelin and oligodendrocyte lineage progression in ASM knockout mice. We show that early-onset dysmyelination results from compromised oligodendrocyte maturation driven by aberrant sphingomyelin-mediated signaling. Transcriptomic profiling revealed that mature oligodendrocytes in these mice retain a gene expression signature similar to oligodendrocyte precursor cells, indicating a differentiation arrest. The cell adhesion molecule CD44 remained significantly upregulated in mature ASMko oligodendrocytes. Pharmacological inhibition of CD44 with verbascoside rescued oligodendroglial maturation in primary culture. Verbascoside administration in vivo restored myelin integrity and improved motor behavior. These findings establish that sphingomyelin homeostasis is critical for oligodendrocyte maturation and identify myelin defects as both primary pathological triggers and therapeutic targets for ASMD with neurologic symptoms.

Animals↗

PubMed2026

COMMD9-regulated endothelial cell abnormality-induced hypercoagulability is associated with Budd-Chiari syndrome.

BACKGROUND: Budd-Chiari syndrome (BCS) presents diagnostic and treatment challenges owing to its insidious onset. Genetic variants associated with BCS vary geographically; in Asian populations, the condition is primarily caused by membranous obstruction composed of endothelial cells (ECs). A better understanding of the genetic pathogenesis of membranous BCS may offer new insights into disease mechanisms. METHODS: This study employed whole-exome sequencing to identify candidate genes responsible for EC abnormalities in 485 patients with membranous BCS and 329 patients with vascular malformations (VaMs). Functional investigations were conducted to validate the selected genes in vitro and in vivo. RESULTS: Whole-exome data revealed that the frequency of variants in the vascular function-related KLHDC2 exceeded that of JAK2 in BCS. Knockdown of KLHDC2 promoted adhesion and suppressed proliferation of ECs. In addition, 92 genes enriched for rare variants overlapped between BCS and VaMs. Systems biology analysis revealed two gene clusters, including COMMD9, enriched in proteins intolerant to loss-of-function mutations. Furthermore, suppression of COMMD9 impaired EC migration and tube formation, inhibited subintestinal angiogenic sprouting in zebrafish, and elevated EC adhesion. Transcriptomic analysis linked COMMD9 to EC abnormalities via the PI3K-Akt pathway. Commd9 knockdown promoted venous hypercoagulability in vivo following drug or ligation-induced stenosis. CONCLUSIONS: These findings indicate that multiple rare genetic variants, particularly in COMMD9, are involved in the development of membranous BCS by regulating hypercoagulability induced by EC abnormalities. These findings may help guide future clinical research towards improved understanding and treatment of BCS.

Budd–Chiari syndrome↗