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Human germline biallelic complete NFAT1 deficiency causes the triad of joint contractures, osteochondromas, and susceptibility to B cell malignancy

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193415 | GEO | 2023/02/20

REPOSITORIES: GEO

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Human germline biallelic complete NFAT1 deficiency causes the triad of joint contractures, osteochondromas, and susceptibility to B cell malignancy [Single]

Project description:We isolated peripheral blood mononuclear cells from whole blood from an NFAT1 deficient patient and 5 healthy controls. Cells were either treated with PMA (50ng/mL) + 1uM Ionomycin for 4 hours, or left untreated. Cells were then isolated in nanowells, and incubated with single mRNA-capture beads. mRNA from these beads were used for library preparation and sequenced. Raw counts were used for clustering analysis and differential expression. This analysis pointed to defects in NFAT1 deficient patient's B-cells and T-cells that could be contributing the observed B-cell malignancy

2023-02-20 | GSE193410 | GEO

Human germline biallelic complete NFAT1 deficiency causes the triad of joint contractures, osteochondromas, and susceptibility to B cell malignancy [Bulk]

Project description:We isolated chondrocytes from an NFAT1 deficient patients osteochondromas surgically removed from the promixal tibia. The cells were either infected with empty vector (labeled "patient") or WT-NFATC2 (labeled "rescue"). We then conducted differential expression, and gene-set enrichment analysis and determined that inflammatory and cell proliferation signals were higher in "patient" chondrocytes

2023-02-20 | GSE193414 | GEO

Human germline biallelic complete NFAT1 deficiency causes the triad of joint contractures, osteochondromas, and susceptibility to B cell malignancy

Project description:Human germline biallelic complete NFAT1 deficiency causes the triad of joint contractures, osteochondromas, and susceptibility to B cell malignancy

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Human germline biallelic complete NFAT1 deficiency causes the triad of joint contractures, osteochondromas, and susceptibility to B cell malignancy [Single]

Project description:Human germline biallelic complete NFAT1 deficiency causes the triad of joint contractures, osteochondromas, and susceptibility to B cell malignancy [Single]

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Human germline biallelic complete NFAT1 deficiency causes the triad of joint contractures, osteochondromas, and susceptibility to B cell malignancy [Bulk]

Project description:Human germline biallelic complete NFAT1 deficiency causes the triad of joint contractures, osteochondromas, and susceptibility to B cell malignancy [Bulk]

| PRJNA796050 | ENA

Excessive mechanotransduction in sensory neurons causes joint contractures.

Project description:Distal arthrogryposis (DA) is a collection of rare disorders that are characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal system. However, gain-of-function mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 (DA5) through unknown mechanisms. We show that expression of a gain-of-function PIEZO2 mutation in proprioceptive sensory neurons that mainly innervate muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects through increased activity within the peripheral nervous system during postnatal development. Furthermore, botulinum toxin (Botox) and a dietary fatty acid that modulates PIEZO2 activity reduce DA5-like deficits. This reveals a role for somatosensory neurons: Excessive mechanosensation within these neurons disrupts musculoskeletal development.

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Joint capsule matrix turnover in a rabbit model of chronic joint contractures: Correlation with human contractures.

Project description:To evaluate changes in matrix molecules of the joint capsule, the right knees of 24 skeletally mature female NZW rabbits were immobilized while the contralateral limb served as an unoperated control. The immobilization was discontinued at 8 weeks and the rabbits were divided among four groups (n = 6) based on the number of weeks the right knees were remobilized: 0, 8, 16, or 32. Three rabbits (six knees) that did not have operations provided normal control joint capsules. The mRNA levels for collagen types I, II, and III, and MMP-1 and -13 were significantly increased in the joint capsules of the contracture knees in all groups when compared to normal and contralateral limb joint capsules. In contrast, the mRNA levels for TIMP-1, -2, and -3 were decreased in the joint capsules of the contracture knees in all groups when compared to normal and contralateral limb joint capsules. The mRNA levels for lumican and decorin were increased in the joint capsules of the contracture knees in all groups when compared to normal capsules. Many of the changes observed in this animal model are similar to those observed in human joint capsules from posttraumatic elbow contractures, supporting the value of this rabbit model.

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Germline biallelic mutation affecting the transcription factor Helios causes pleiotropic defects of immunity.

Project description:Helios, a member of the Ikaros family of transcription factors, is predominantly expressed in developing thymocytes, activated T cells, and regulatory T cells (Tregs). Studies in mice have emphasized its role in maintenance of Treg immunosuppressive functions by stabilizing Foxp3 expression and silencing the Il2 locus. However, its contribution to human immune homeostasis and the precise mechanisms by which Helios regulates other T cell subsets remain unresolved. Here, we investigated a patient with recurrent respiratory infections and hypogammaglobulinemia and identified a germline homozygous missense mutation in IKZF2 encoding Helios (p.Ile325Val). We found that HeliosI325V retains DNA binding and dimerization properties but loses interaction with several partners, including epigenetic remodelers. Whereas patient Tregs showed increased IL-2 production, patient conventional T cells had decreased accessibility of the IL2 locus and consequently reduced IL-2 production. Reduced chromatin accessibility was not exclusive to the IL2 locus but involved a variety of genes associated with T cell activation. Single-cell RNA sequencing of peripheral blood mononuclear cells revealed gene expression signatures indicative of a shift toward a proinflammatory, effector-like status in patient CD8+ T cells. Moreover, patient CD4+ T cells exhibited a pronounced defect in proliferation with delayed expression of surface checkpoint inhibitors, suggesting an impaired onset of the T cell activation program. Collectively, we identified a previously uncharacterized, germline-encoded inborn error of immunity and uncovered a cell-specific defect in Helios-dependent epigenetic regulation. Binding of Helios with specific partners mediates this regulation, which is ultimately necessary for the transcriptional programs that enable T cell homeostasis in health and disease.

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TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Project description:Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

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Arthrogryposis Multiplex Congenita: Multiple Congenital Joint Contractures.

Project description:Arthrogryposis multiplex congenita (AMC) is a syndrome characterized by nonprogressive multiple congenital joint contractures. The etiology of disease is multifactorial; it is most commonly suspected from absent fetal movements and genetic defects. AMC affects mainly limbs; also it might present with other organs involvement. It is crucial that the diagnosis of AMC should be kept in mind by musculoskeletal physicians in newborns with multiple joint contractures and patients must begin rehabilitation in early stage after accurate diagnosis in terms of functional independence. We present the diagnosis, types, clinical features, and treatment approaches of this disease in our case with literature reviews.

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