Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations.
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ABSTRACT:
SUBMITTER: Jeremiah N
PROVIDER: S-EPMC4348945 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Intestinal immune homeostasis is preserved by commensal bacteria interacting with the host to generate a balanced array of cytokines that are essential for wound repair and for combatting infection. Inflammatory bowel disease (IBD), which can lead to colitis-associated cancer (CAC), is thought to involve chronic microbial irritation following a breach of the mucosal intestinal epithelium. However, the innate immune pathways responsible for regulating these inflammatory processes remain to be fully clarified. Here, we show that commensal bacteria influence STING signaling predominantly in mononuclear phagocytes to produce both pro-inflammatory cytokines as well as anti-inflammatory IL-10. Enterocolitis, manifested through loss of IL-10, was completely abrogated in the absence of STING. Intestinal inflammation was less severe in the absence of cGAS, possibly suggesting a role for cyclic dinucleotides (CDNs) indirectly regulating STING signaling. Our data shed insight into the causes of inflammation and provide a potential therapeutic target for prevention of IBD.
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Project description:STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.
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Project description:BACKGROUND Familial diarrheas are mostly severe recessive diseases. Here we describe the clinical picture and dominant genetic cause of a novel disease in 32 members of a Norwegian family. The chronic diarrhea is of early onset, relatively mild, and is combined with increased susceptibility to intestinal inflammation, ileus and oesophagitis. METHODS Whole genome SNP-analysis was used to identify a single candidate locus for dominant diarrhea on chromosome 12, followed by sequencing of the GU2CY gene. This encodes guanylyl cyclase 2C, an intestinal receptor for bacterial heat-stable enterotoxins and the peptides uroguanylin and guanylin. Functional studies of a missense mutation were performed after heterologous expression of the mutant receptor in HEK293T cells. The therapeutic response to metformin, an inhibitor of the cystic fibrosis transmembrane regulator (CFTR), was investigated in 5 patients. RESULTS We identified heterozygosity for the first described pathogenic human mutation (c.2519G>T ) in the GUCY2C gene. The mutant receptor showed increased cGMP production in response to its ligands. This may cause hyperactivation of the CFTR and consequent increased chloride and water secretion from the enterocytes, resulting in chronic diarrhea. Treatment with the CFTR-inhibitor metformin significantly reduced the frequency of stools in affected individuals by 34-45%. CONCLUSIONS Increased GC-C signaling disturbs normal bowel function, as shown by the diverse symptoms in our patients, and seems to have a pro-inflammatory effect, either through increased Cl- secretion or additional effects of elevated cellular cGMP. The importance of genetic variants in the GC-C-CFTR-pathway for conditions like Crohn’s disease and IBS should be further explored. Linkage analysis was performed (Allegro v 2.0) using Affymetrix 250K SNP arrays according to the manufacturer's directions on DNA extracted from peripheral blood samples. This accession number contains the data for 25 individuals of family branch A in the article.
2012-04-09 | E-GEOD-31260 | biostudies-arrayexpress
Project description:BACKGROUND:Familial chilblain lupus (FCL) is a rare, chronic form of cutaneous lupus erythematosus, which is characterized by painful bluish-red inflammatory cutaneous lesions in acral locations. Mutations in TREX1, SAMHD1 and STING have been described in FCL patients. Less than 10 TREX1 mutation positive FCL families have been described in the literature. CASE PRESENTATION:Genetic study was performed in a large, nonconsanguineous Chinese family with 13 members over 4 generations affected by chilblain lupus. Whole exome sequencing was performed for the index patient. Significant variant detection was subsequently validated by resequencing using Sanger sequencing in the index patient and other family members. A novel pathogenic mutation TREX1 p.Asp18His was iditified in the index patient. The mutation was present in affected individuals and was absent in non-affected individuals in the familiy. CONCLUSIONS:We present a four-generation Chinese family with FCL caused by a novel heterozygous mutation TREX1 p.Asp18His, which had been reported in a patient with Aicardi-Goutie'res syndrome. This is the first reported Chinese family with FCL based on mutation in TREX1.
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Project description:BACKGROUND Familial diarrheas are mostly severe recessive diseases. Here we describe the clinical picture and dominant genetic cause of a novel disease in 32 members of a Norwegian family. The chronic diarrhea is of early onset, relatively mild, and is combined with increased susceptibility to intestinal inflammation, ileus and oesophagitis. METHODS Whole genome SNP-analysis was used to identify a single candidate locus for dominant diarrhea on chromosome 12, followed by sequencing of the GU2CY gene. This encodes guanylyl cyclase 2C, an intestinal receptor for bacterial heat-stable enterotoxins and the peptides uroguanylin and guanylin. Functional studies of a missense mutation were performed after heterologous expression of the mutant receptor in HEK293T cells. The therapeutic response to metformin, an inhibitor of the cystic fibrosis transmembrane regulator (CFTR), was investigated in 5 patients. RESULTS We identified heterozygosity for the first described pathogenic human mutation (c.2519G>T ) in the GUCY2C gene. The mutant receptor showed increased cGMP production in response to its ligands. This may cause hyperactivation of the CFTR and consequent increased chloride and water secretion from the enterocytes, resulting in chronic diarrhea. Treatment with the CFTR-inhibitor metformin significantly reduced the frequency of stools in affected individuals by 34-45%. CONCLUSIONS Increased GC-C signaling disturbs normal bowel function, as shown by the diverse symptoms in our patients, and seems to have a pro-inflammatory effect, either through increased Cl- secretion or additional effects of elevated cellular cGMP. The importance of genetic variants in the GC-C-CFTR-pathway for conditions like Crohn’s disease and IBS should be further explored.
2012-04-10 | GSE31260 | GEO
Project description:In developed countries, the lifetime risk of developing colorectal cancer (CRC) is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility.MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies). Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors.Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I) in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in <1% in the general population. The threonine at amino acid position 992 lies in the tyrosine kinase domain of MET and a change to isoleucine at this position has been shown to promote metastatic behavior in cell-based models. The average age of CRC diagnosis in patients in this study is 63 years in mutation carriers, which is 8 years earlier than the general population average for CRC.Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will be an important extension of this work to define the clinical significance.
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Project description:Inherited forms of cataract are a clinically important and genetically heterogeneous cause of visual impairment that usually present at an early age with or without systemic and/or other ocular abnormalities. Here we have identified a new locus for inherited cataract and high-tension glaucoma with variable anterior segment defects, and characterized an underlying mutation in the gene coding for transient receptor potential cation channel, subfamily M, member-3 (TRPM3, melastatin-2). Genome-wide linkage analysis mapped the ocular disease locus to the pericentric region of human chromosome 9. Whole exome and custom-target next-generation sequencing detected a heterozygous A-to-G transition in exon-3 of TRPM3 that co-segregated with disease. As a consequence of alternative splicing this missense mutation was predicted to result in the substitution of isoleucine-to-methionine at codon 65 (c.195A>G; p.I65 M) of TRPM3 transcript variant 9, and at codon 8 (c.24A>G; p.I8 M) of a novel TRPM3 transcript variant expressed in human lens. In both transcript variants the I-to-M substitution was predicted in silico to exert damaging effects on protein function. Furthermore, transient expression studies of a recombinant TRPM3-GFP reporter product predicted that the I-to-M substitution introduced an alternative translation start-site located 89 codons upstream from the native initiator methionine found in eight other TRPM3 transcript variants (1-8). Collectively, these studies have provided the first evidence that TRPM3 is associated with inherited ocular disease in humans, and further provide support for the important role of this cation channel in normal eye development.
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