Bulk RNA sequencing analysis of a patient with an immunodeficiency caused by a novel homozygous missense variant in HYOU1
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PROVIDER: PRJEB95011 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we report a patient with a novel homozygous variant in HYOU1 (NM_001130991.3:c.1331C>A, p.Pro444His), who was born to related parents and presented with combined immunodeficiency, failure to thrive, and hypoglycemia. We undertook a multiomics analysis combining transcriptomics, proteomics, and single cell RNA sequencing analyses, demonstrating a drastic reduction in B cell count and hypogranulation of neutrophils in conformity with the findings of immunophenotyping. Additionally, we showed that despite the HYOU1 transcript being expressed and stable, the patient has HYOU1 deficiency at the protein level. Moreover, single cell RNA sequencing of bone marrow revealed that the B cell differentiation process is prematurely arrested at pre-pro B cell stage. The present dataset corresponds to the single-cell RNAseq performed on unsorted cells obtained from peripheral blood and bone marrow samples of the patient and healthy controls (three biological replicates for the patient and four controls)
2025-01-29 | E-MTAB-14786 | biostudies-arrayexpress
Project description:ZBTB24 is a member of a protein family that includes a Broad-Complex, Tramtrack, and Bric a Brac (BTB) domain, which functions in protein-protein interactions. ZBTB24, a transcription factor, binds its targets through its C-terminus zinc finger (ZF) domain. Biallelic ZBTB24 mutations lead to the rare autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies subtype 2 (ICF2) syndrome. The majority of the ICF2 patients have biallelic loss of function alleles. The remaining patients have missense variants in their ZF domain. As a consequence, one of ZBTB24’s targets, CDCA7, the gene responsible for ICF3, is not expressed in ICF2 patient cells. Similar to all subtypes of ICF syndrome, ZBTB24 pathogenic mutations lead to significant DNA hypomethylation throughout the genome. Here we describe a patient with a homozygous variant with unknown significance (VUS), p.Val43Leu, in the BTB domain of ZBTB24. To examine the pathogenicity of this change, we determined DNA methylation levels and patterns in patient blood and lymphoblastoid cells (LCLs). We found significant hypomethylation throughout the patient’s genome, with a methylation pattern identical to that of other ICF2 patients, albeit with less severe hypomethylation. Importantly, the satellite repeats were significantly hypomethylated, a hallmark of ICF syndrome. We found that the p.Val43Leu change significantly reduces the protein’s stability, resulting in very low levels of CDCA7 expression in the patient-derived LCLs. Additionally ,the nuclear pattern of localization of ZBTB24 was disrupted due to this amino acid change. Thus, we demonstrate for the first time that biallelic missense variants in the BTB domain of ZBTB24, can disrupt the normal functionality of the protein and lead to ICF2 syndrome.
2025-11-30 | GSE249219 | GEO
Project description:Through BioID and mass spectrometry, we investigated SIT1 interactome in a patient with a homozygous SIT1 splice-site variant leading to immunodeficiency and lymphoma. SIT1, previously identified as a negative regulator of T-cell activation, was found to interact with vesicle trafficking proteins, including components of the SCAR/WAVE complex, TRAPP complex, and clathrin-coated pits.
2025-01-08 | MSV000096801 | MassIVE
Project description:Aims: Pathogenic truncating variants in the largest human protein TITIN are a leading cause of dilated cardiomyopathy. Because of the size of the gene encoding TITIN, many missense variations are identified. These are difficult to evaluate in genetic testing, as even individually rare variants are common in aggregate in normal populations. While the majority will be benign, a small subset is pathogenic, but distinction is challenging. Here, we describe the generation of a mouse model to investigate the underlying disease mechanism of a previously reported TITIN A178D missense variant identified in a family with non-compaction and dilated cardiomyopathy. Methods and Results: Heterozygous and homozygous mice carrying the TITIN A178D missense variant were characterised in vivo. Heterozygous mice had no detectable phenotype at any time point observed (up to 1 year). By contrast, homozygous mice developed dilated cardiomyopathy from 3 months. Chronic adrenergic stimulation aggravated the phenotype. Targeted transcript profiling revealed induction of the fetal gene programme and hypertrophic signalling pathways in homozygous mice, and these were confirmed at the protein level. Unsupervised proteomics identified down-regulation of TELETHONIN and FOUR-AND-A-HALF LIM DOMAIN 2, as well as the up-regulation of heat shock proteins and MYELOID LEUKEMIA FACTOR 1. Loss of TELETHONIN from the cardiac Z-disc was accompanied by proteasomal degradation; however, TELETHONIN also accumulated in the cytoplasm. In parallel, a proteo-toxic response was observed in the mice. Conclusions: We have shown that the TITIN A178D missense variant is pathogenic in homozygous mice, resulting in cardiomyopathy. We also provide evidence of the disease mechanism. Because the TITIN A178D variant abolishes binding of TELETHONIN, this leads to its abnormal cytoplasmic accumulation. Subsequent degradation of TELETHONIN by the proteasome results in proteasomal overload, and activation of a proteo-toxic response. The latter appears to be a driving factor for the cardiomyopathy observed in the mouse model.
2021-03-01 | PXD020390 | Pride
Project description:1 Novel Missense Variants in Patients with Primary Immunodeficiency and Immune dysregulation
| PRJEB46587 | ENA
Project description:Determining the pathogenicity of human genetic variants is a critical challenge, and functional assessment is often the only option. Experimentally characterizing millions of possible missense variants in thousands of clinically important genes will likely require generalizable, scalable assays. We previously developed Variant Abundance by Massively Parallel Sequencing (VAMP-seq), which measures the effects of thousands of missense variants of a protein on intracellular abundance in a single experiment. Here, we reapplied VAMP-seq to quantify the abundances of additional PTEN missense variants which were missing from the original experiment.
2021-09-13 | GSE159469 | GEO
Project description:A single TTN point mutation- a missense variant ( TTN-T32756I) can impair sarcomere integrity and lead to atrial electrical remodeling, increasing AF- A link that needs investigation
2025-12-08 | GSE312917 | GEO
Project description:Inhibitor of nuclear factor kappa B kinase alpha (IKKα) is critical for p100/NF-κB2 phosphorylation and processing into p52 and activation of the noncanonical NF-κB pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKKα. The mutation preserves IKKα kinase activity but abolishes the interaction of IKKα with its activator NF-κB–inducing kinase and impairs lymphotoxin-β–driven p100/NF-κB2 processing and VCAM1 expression. Homozygous IKKαY580C/Y580C mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRVβ repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKKα deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.
| S-EPMC8930078 | biostudies-literature
Project description:A Titin Missense Variant Causes Atrial Fibrillation
| PRJNA1377605 | ENA
Project description:The single nucleotide polymorphism rs13166360, causing a substitution of valine 147 to leucine in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that this missense mutation diminishes ADCY2 activity by altering its subcellular localization. Mice homozygous for the leucine variant display signs of a mania-like state accompanied by cognitive impairments. Mutant mice are hypersensitive to amphetamine and mania-like behaviors are responsive to lithium treatment. Exposure to chronic social defeat stress switches homozygous leucine variant carriers from a mania- to a depressive-like state. Single-cell RNA-seq revealed widespread expression of ADCY2 in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate ADCY2 as a BD risk gene providing insights into underlying disease mechanisms potentially opening novel avenues for therapeutic intervention strategies.
2024-12-26 | GSE214733 | GEO