Tumoural soft tissue calcification in Down syndrome: association with heterozygous germline SAMD9 mutation and hyperactive type I interferon signaling.
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ABSTRACT:
SUBMITTER: Deigendesch N
PROVIDER: S-EPMC7820359 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
Publications
Tumoural soft tissue calcification in Down syndrome: association with heterozygous germline SAMD9 mutation and hyperactive type I interferon signaling.
Deigendesch Nikolaus N Hirsiger Julia R JR Bigler Marc B MB Ghosh Adhideb A Harder Dorothee D Jauch Annaïse A Espinosa Joaquin M JM Recher Mike M Navarini Alexander A Daikeler Thomas T Berger Christoph T CT
Rheumatology (Oxford, England) 20201101 11
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Project description:Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A, and this occurred through suppression of IFN-responsive transcription factor activity. Moreover, we discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. Kinase inhibition altered splicing in pathway-specific ways and selectively affected IFN-responsive gene splicing in T21 cells. To further probe Mediator kinase function, we completed cytokine screens and untargeted metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways, including broad up-regulation of anti-inflammatory lipid mediators. Elevated levels of lipid mediators persisted at least 24hr after Mediator kinase inhibition, and many identified lipids serve as ligands for nuclear receptors (e.g. PPAR, LXR) or G-protein coupled receptors (GPCRs; e.g. FFAR4). Notably, ligand-dependent activation of these GPCRs or nuclear receptors will propagate anti-inflammatory signaling pathways and gene expression programs, and this mechanistic link suggests that metabolic changes caused by CDK8/CDK19 inhibition can durably and independently suppress pro-inflammatory IFN responses. Collectively, our results establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions.
| S-EPMC10349994 | biostudies-literature
Project description:Individuals with Down syndrome have a increased likelihood of suffering from inflammatory and autoimmune conditions, due to the presence of four interferon receptors on chromosome 21. Transcription of genes plays a key role in the interferon response, and the Mediator kinases, CDK8 and CDK19, are essential in potentiating this transcription. Given the role CDK8/19 play in the interferon response, and the fact that selective inhibitors of these kinases exist (such as Cortistatin A), it is possible that targetting Mediator kinase activity may alleviate symptoms of chronic inflammation in Down syndrome.
2023-09-12 | GSE220652 | GEO
Project description:Individuals with Down syndrome have a increased likelihood of suffering from inflammatory and autoimmune conditions, due to the presence of four interferon receptors on chromosome 21. Transcription of genes plays a key role in the interferon response, and the Mediator kinases, CDK8 and CDK19, are essential in potentiating this transcription. Given the role CDK8/19 play in the interferon response, and the fact that selective inhibitors of these kinases exist (such as Cortistatin A), it is possible that targetting Mediator kinase activity may alleviate symptoms of chronic inflammation in Down syndrome.
2025-02-04 | GSE263239 | GEO
Project description:Individuals with Down syndrome have a increased likelihood of suffering from inflammatory and autoimmune conditions, due to the presence of four interferon receptors on chromosome 21. Transcription of genes plays a key role in the interferon response, and the Mediator kinases, CDK8 and CDK19, are essential in potentiating this transcription. Given the role CDK8/19 play in the interferon response, and the fact that selective inhibitors of these kinases exist (such as Cortistatin A), it is possible that targetting Mediator kinase activity may alleviate symptoms of chronic inflammation in Down syndrome.
2025-01-01 | GSE249548 | GEO
Project description:Individuals with Down syndrome have a increased likelihood of suffering from inflammatory and autoimmune conditions, due to the presence of four interferon receptors on chromosome 21. Transcription of genes plays a key role in the interferon response, and the Mediator kinases, CDK8 and CDK19, are essential in potentiating this transcription. Given the role CDK8/19 play in the interferon response, and the fact that selective inhibitors of these kinases exist (such as Cortistatin A), it is possible that targetting Mediator kinase activity may alleviate symptoms of chronic inflammation in Down syndrome.
2024-09-01 | GSE249549 | GEO
Project description:Erythrocytosis or polycythemia refers to a true or apparent increase in hemoglobin or hematocrit. When no etiology of erythrocytosis is identified, people are diagnosed with "idiopathic erythrocytosis" (IE). The identification of new contributing genes has recently improved the diagnostic workup of IE. As such mutations within the SH2B3 gene, which codes for the LNK protein and negatively regulates the JAK-STAT pathway, have been identified in cases diagnosed as IE. This reports describes the presence of a previously undescribed germline SH2B3 variant p.(Thr335ArgfsTer4) within IE and emphasizes the advantages of gene panel sequencing as second step in the diagnostic work-up.
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Project description:Sterile α motif domain-containing protein 9 (SAMD9) is a regulatory protein centrally involved in cell proliferation and apoptosis. Mapped to 7p21.2, variants in SAMD9 have been reported in <50 pediatric cases worldwide, typically with early lethality. Germline gain-of-function SAMD9 variants are associated with MIRAGE syndrome (myelodysplasia, infection, restricted growth, adrenal hypoplasia, genital anomalies, and enteropathy). Spalt like transcription factor 1 (SALL1) is a zinc finger transcriptional repressor located at 16q12.1 where only two transcript variants in SALL1 are known. RUNX2 (6p21.1) encodes a nuclear protein with a Runt DNA-binding domain critical for osteoblastic differentiation, skeletal morphogenesis, and serves as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. RUNX2 and SALL1 are thus both "master regulators" of tissue organization and embryo development. Here, we describe exome sequencing and copy number variants in two previously unknown mutations-R824Q in SAMD9, and Q253H in SALL1. A multiexon 3' terminal duplication of RUNX2 not previously encountered is also reported. This is the first known phenotype assessment for an intersection of all three variants in a healthy 46,XX adult. Focusing on developmental progress, ultrastructural renal anatomy, and selected reproductive aspects, we describe this unique genotype diagnosed incidentally during coronavirus disease 2019 (COVID-19) illness. Individually, disruption in SAMD9, RUNX2, or SALL1 would be expected to give a bleak prognosis. However, this variant convergence appears to dampen severe pathology perhaps by cross-gene silencing of effects normally deleterious when such changes occur alone.
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Project description:Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n?=?10), congenital amegakaryocytic thrombocytopenia (n?=?1), and dyskeratosis congenita (n?=?1). Exome sequencing revealed heterozygous mutations in SAMD9 (n?=?6) or SAMD9L (n?=?6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.
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Project description:Familial tumoral calcinosis (FTC) is a rare autosomal recessive disorder characterized by the progressive deposition of calcified masses in cutaneous and subcutaneous tissues, which results in painful ulcerative lesions and severe skin and bone infections. Two major types of FTC have been recognized: hyperphosphatemic FTC (HFTC) and normophosphatemic FTC (NFTC). HFTC was recently shown to result from mutations in two different genes: GALNT3, which codes for a glycosyltransferase, and FGF23, which codes for a potent phosphaturic protein. To determine the molecular cause of NFTC, we performed homozygosity mapping in five affected families of Jewish Yemenite origin and mapped NFTC to 7q21-7q21.3. Mutation analysis revealed a homozygous mutation in the SAMD9 gene (K1495E), which was found to segregate with the disease in all families and to interfere with the protein expression. Our data suggest that SAMD9 is involved in the regulation of extraosseous calcification, a process of considerable importance in a wide range of diseases as common as atherosclerosis and autoimmune disorders.
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