Homozygous IL37 mutation leads to infantile inflammatory bowel disease
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ABSTRACT:
PROVIDER: PRJNA635708 | ENA |
REPOSITORIES: ENA
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Project description:Homozygous IL37 mutation leads to infantile inflammatory bowel disease
| PRJNA635709 | ENA
Project description:Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function IL37 mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell-derived macrophages from the patient revealed an activated macrophage phenotype, which is more prone to lipopolysaccharide and IL-1β stimulation, resulting in hyperinflammatory tumor necrosis factor production. Insights from this patient will not only shed light on monogenic contributions of I-IBD but may also reveal the significance of the IL-18 and IL-37 axis in colonic homeostasis.
| S-EPMC7958356 | biostudies-literature
Project description:Introduction: Although sequence variants in FAT1 have been identified in patients with distinct renal disease, definitive proof of causality in human disease is meager. Methods: A 35-year-old Chinese female with microscopic hematuria and proteinuria underwent a renal biopsy to identify the underlying cause. Whole-exome sequencing (WES) with homozygosity mapping revealed genetic factors, and patient-derived primary urinary epithelial cells confirmed the renal agenesis phenotype. RNA sequencing, immunofluorescence staining, and immunoblotting were used to explore the mechanisms involved. Results: The patient, whose parents are cousins, exhibited a syndrome featuring ptosis, corneal dystrophy, macular degeneration and right feet syndactyly, with glomerulotubular nephropathy. A homozygous frameshift mutation in FAT1 (NM_005245: c.7444_7445delGT) was identified. Structural prediction, immunohistochemistry, and Western blot analyses confirmed that the mutation caused translational repression of FAT1. RNA-seq analysis revealed significant dysregulation of cell adhesion and the Rap1 signaling pathway. Immunofluorescence showed a marked loss of intercellular β-catenin junctions and cytoskeletal disruption in patient-derived primary urinary epithelial cells. Pull-down assays demonstrated that these effects were associated with a reduction in activated Rap1 levels. Conclusion: This study presents compelling evidence that the homozygous FAT1 frameshift mutation (c.7444_7445delGT, p.Val2482fs) is causally associated with nephropathy and congenital anomalies. The mutation likely leads to the degradation of transcribed mRNA, which in turn impairs protein expression. These findings underscore the critical role of FAT1 in renal development and offer new insights into the molecular mechanisms underlying these conditions.
2025-11-13 | GSE282237 | GEO
Project description:Novel Homozygous FAT1 Mutation Causes glomerulotubular nephropathy in Asian adult
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Project description:The goal of this study was to identify new mutations in the ENPP1 gene that produce infantile arterial calcification and fetal demise. A stillborn (proband) was diagnosed with infantile arterial calcification. Mutations in the ENPP1 gene account for ~80% of the cases of infantile arterial calcification through loss of function in both alleles (recessive inheritance).
2011-01-26 | GSE26860 | 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:Filamin C (encoded by the FLNC gene) is a large actin-cross-linking protein involved in shaping the actin cytoskeleton in response to signaling events both at the sarcolemma and at myofibrillar Z-discs of cross-striated muscle cells. Multiple mutations in FLNC are associated with myofibrillar myopathies of autosomal dominant inheritance. Here, we describe a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous FLNC mutation affecting the rod domain of the protein. To demonstrate pathogenicity of this homozygous FLNC-mutation described, ultra-morphological, proteomic and functional investigations were performed in addition to immunological studies of known marker proteins for dominant filaminopathies. Our results showed that the mutant protein is expressed to similar quantities as the wildtype variant in control skeletal muscle fibres, alters the proteomic signature of quadriceps muscle, and results in the presence of ultrastructural perturbations. Moreover, comparable findings for filaminopathy marker proteins were found in both, our homozygous and a dominant case. The mutant protein is less stable and more prone to degradation by proteolytic enzymes than the wildtype variant. These combined findings extend the currently recognized clinical, genetic and biochemical spectrum of filaminopathies. The unusual congenital presentation of the disease indicates that homozygosity for a mutation in filamin C severely aggravates the phenotype.
2020-07-24 | PXD016657 | Pride
Project description:Primary ovarian insufficiency (POI) is a complex disorder that affects many genes and the underlying molecular mechanisms remain to be fully elucidated. In this study, a homozygous point mutation, c.808C>T, in the DAZL gene of a POI patient was identified. This homozygous variant causes a C-terminal truncation of DAZL and down-regulation of germ-line gene NANOS3 expression, among other dysregulated genes, in human primordial germ cells (hPGCs) in vitro. Mechanistically, we discovered that the truncated DAZL had defects in regulating mRNA translation for NANOS3, VASA, and SYCP3 - all essential for gametogenesis. Additionally, the truncated DAZL showed impaired interaction with Poly(A)-binding proteins (PABPs), a crucial component of the translation initiation complex. At the cellular level, the truncated mutation resulted in increased apoptosis of in vitro hPGCs. Our findings reveal that the c.808C>T mutation in DAZL causes dysregulated expressions of many genes, increases germ cell apoptosis and ultimately leads to POI.
2023-10-18 | GSE245155 | GEO
Project description:A Dominant mutation in Dnmt1 leads epigenetic changes (rrbs)
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Project description:A Dominant mutation in Dnmt1 leads epigenetic changes (Emseq)
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