Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Flanagan SE
PROVIDER: S-EPMC4129488 | biostudies-literature | 2014 Aug
REPOSITORIES: biostudies-literature
Publications
Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.
Flanagan Sarah E SE Haapaniemi Emma E Russell Mark A MA Caswell Richard R Allen Hana Lango HL De Franco Elisa E McDonald Timothy J TJ Rajala Hanna H Ramelius Anita A Barton John J Heiskanen Kaarina K Heiskanen-Kosma Tarja T Kajosaari Merja M Murphy Nuala P NP Milenkovic Tatjana T Seppänen Mikko M Lernmark Åke Å Mustjoki Satu S Otonkoski Timo T Kere Juha J Morgan Noel G NG Ellard Sian S Hattersley Andrew T AT
Nature genetics 20140720 8
Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome. ...[more]
Similar Datasets
Project description:Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.
| S-EPMC4304103 | biostudies-literature
Project description:We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and ?-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.
| S-EPMC5065661 | biostudies-literature
Project description:BACKGROUND: Gastric cancer remains a leading cause of cancer deaths worldwide. Genetic factors, including germline mutations in E-cadherin (CDH1, MIM#192090) in hereditary diffuse gastric cancer (HDGC, MIM#137215), are implicated in this disease. Family studies have reported CDH1 germline mutations in HDGC but the role of CDH1 germline mutations in the general population remains unclear. AIMS: To examine the frequency of CDH1 germline mutations in a population-based series of early-onset gastric cancer (EOGC <50 years old). METHODS: 211 cases of EOGC were identified in Central-East Ontario region from 1989 to 1993, with archival material and histological confirmation of non-intestinal type gastric cancer available for 81 subjects. Eligible cases were analysed for CDH1 germline mutations by single-strand conformation polymorphism, variants were sequenced, and tumours from cases with functional mutations were stained for E-cadherin (HECD-1) using immunohistochemistry. RESULTS: 1155 (89%) of 1296 polymerase chain reactions amplified successfully. One new germline deletion (nt41delT) was identified in a 30-year-old patient with isolated cell gastric cancer. The overall frequency of germline CDH1 mutations was 1.3% (1/81) for EOGC and 2.8% (1/36) for early-onset isolated cell gastric cancer. CONCLUSION: This is the first population-based study, in a low-incidence region, of genetic predisposition to gastric cancer. Combined with our previous report of germline hMLH1 mutations in two other subjects from this series, it is suggested that 2-3% of EOCG cases in North Americans may be owing to high-risk genetic mutations. These data should inform cancer geneticists on the utility of searching for specific genetic mutations in EOGC.
| S-EPMC2563190 | biostudies-literature
Project description:To identify novel genetic bases of early-onset epithelial ovarian tumors, we used the trio exome sequencing strategy in a patient without familial history of cancer who presented metastatic serous ovarian adenocarcinomas at 21 years of age. We identified a single de novo mutation (c.1157A>G/p.Asn386Ser) within the INHBA gene encoding the ?A-subunit of inhibins/activins, which play a key role in ovarian development. In vitro, this mutation alters the ratio of secreted activins and inhibins. In a second patient with early-onset serous borderline papillary cystadenoma, we identified an unreported germline mutation (c.179G>T/p.Arg60Leu) of the INHA gene encoding the ?-subunit, the partner of the ?A-subunit. This mutation also alters the secreted activin/inhibin ratio, by disrupting both inhibin A and inhibin B biosynthesis. In a cohort of 62 cases, we detected an additional unreported germline mutation of the INHBA gene (c.839G>A/p.Gly280Glu). Our results strongly suggest that inhibin mutations contribute to the genetic determinism of epithelial ovarian tumors.
| S-EPMC4284000 | biostudies-literature
Project description:Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3γ) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n = 1) and YWHAG (n = 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder's etiology and genotype-phenotype correlations.
| S-EPMC5544417 | biostudies-literature
Project description:Germinal heterozygous activating STAT3 mutations represent a novel monogenic defect associated with multi-organ autoimmune disease and, in some cases, severe growth retardation. By using whole-exome sequencing, we identified two novel STAT3 mutations, p.E616del and p.C426R, in two unrelated pediatric patients with IGF-I deficiency and immune dysregulation. The functional analyses showed that both variants were gain-of-function (GOF), although they were not constitutively phosphorylated. They presented differences in their dephosphorylation kinetics and transcriptional activities under interleukin-6 stimulation. Both variants increased their transcriptional activities in response to growth hormone (GH) treatment. Nonetheless, STAT5b transcriptional activity was diminished in the presence of STAT3 GOF variants, suggesting a disruptive role of STAT3 GOF variants in the GH signaling pathway. This study highlights the broad clinical spectrum of patients presenting activating STAT3 mutations and explores the underlying molecular pathway responsible for this condition, suggesting that different mutations may drive increased activity by slightly different mechanisms.
| S-EPMC6143347 | biostudies-literature
Project description:Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li-Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited.We retrospectively reviewed the clinical records of women who underwent genetic testing for suspected germline TP53 mutations and who were diagnosed with breast cancer between 2000 and 2011. The pathological characteristics of the breast tumors from patients testing positive for a mutation (cases) were compared with those testing negative (controls).Patients who tested positive for germlineTP53 mutations (n = 30) were compared with controls (n = 79). Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared with 25% for the controls (P = .0001). Among patients with a mutation, 70% had estrogen receptor- and/or progesterone receptor-positive tumors, compared with 68% in the control group (P = .87). After adjusting for age at breast cancer diagnosis, having a HER2-positive tumor increased the odds of testing positive for a germline TP53 mutation (odds ratio, 6.9; 95% confidence interval, 2.6-18.2). For each yearly increment in age at breast cancer diagnosis, there was decreased likelihood of having a TP53 mutation of 5% (odds ratio, 0.95; 95% confidence interval0.91-0.99).This study suggests an association between germline TP53 mutations and early onset HER2-positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2-targeted therapies, and elucidate some of the molecular pathways involved in breast cancer.
| S-EPMC3527897 | biostudies-literature
Project description:Bloom syndrome is an autosomal recessive disorder characterized by chromosomal instability and increased cancer risk, caused by biallelic mutations in the RECQL-helicase gene BLM. Previous studies have led to conflicting conclusions as to whether carriers of heterozygous BLM mutations have an increased risk to develop colorectal cancer (CRC). We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (≤45 years of age), suggesting an overrepresentation compared to the normal population. Here, we performed targeted sequencing using molecular inversion probes to screen an additional cohort of 185 CRC patients (≤50 years of age) and 532 population-matched controls for deleterious BLM mutations. In total, we identified three additional CRC patients (1.6%) and one control individual (0.2%) that carried a known pathogenic BLM mutation, suggesting that these mutations are enriched in early-onset CRC patients (P = 0.05516). A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P = 0.003534). Analysis of family members of the five BLM mutation carriers with CRC suggests an incomplete penetrance for CRC development. Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance.
| S-EPMC4566092 | biostudies-literature
Project description:BackgroundThe clinical phenotype of DYT6 consists mainly of primary craniocervical dystonia. Recently, the THAP1 gene was identified as the cause of DYT6, where a total of 13 mutations have been identified in Amish-Mennonite and European families.MethodsWe sequenced the THAP1 gene in a series of 362 British, genetically undetermined, primary dystonia patients (78 with focal, 186 with segmental, and 98 with generalized dystonia) and in 28 dystonia-manifesting DYT1 patients and 176 normal control individuals.ResultsNine coding mutations were identified in the THAP1 gene. Two were small deletions, 2 were nonsense, and 5 were missense. Eight mutations were heterozygous, and 1 was homozygous. The main clinical presentation of cases with THAP1 mutations was early-onset (<30 years) dystonia in the craniocervical region or the limbs (8 of 9 patients). There was phenotypic variability with laryngeal or oromandibular dystonia present in 3 cases. Four of 9 THAP1 cases developed generalized dystonia.ConclusionsThe number of THAP1 mutations has been significantly expanded, indicating an uncommon but important cause of dystonia. Coding mutations account for 9 of 362 dystonia cases, indicating a mutation frequency of 2.5% of dystonia cases in the population that we have screened. The majority of cases reported here with THAP1 mutations had craniocervical- or limb-onset segmental dystonia, but we also identified 1 homozygous THAP1 mutation, associated initially with writer's dystonia and then developing segmental dystonia. Three of our patients had a nonsense or frameshift THAP1 mutation and the clinical features of laryngeal or oromandibular dystonia. These data suggest that early-onset dystonia that includes the involvement of the larynx or face is frequently associated with THAP1 mutations.
| S-EPMC2839194 | biostudies-literature
Project description:BACKGROUND:African Americans have both a higher incidence of prostate cancer and greater disease-specific mortality compared with non-Hispanic whites. Historically, the investigation of the contribution of rare genetic variants to prostate cancer in African American men has been hampered by low participation in large genetic studies, particularly those focused on early-onset and familial disease. METHODS:We sequenced 160 genes purported to be involved in carcinogenic pathways in germline DNA samples collected from 96 African American men diagnosed with early-onset prostate cancer (?55 years at diagnosis). REVEL software was used to determine the pathogenic potential of observed missense variants. RESULTS:We observed three protein-truncating mutations, one in BRCA2 and two in BRIP1 in three African American men diagnosed with early-onset prostate cancer. Furthermore, we observed five rare, mostly private, missense variants among four genes (BRCA1, BRCA2, PMS2, and ATM) that were predicted to be deleterious and hence likely pathogenic in our patient sample. CONCLUSIONS:Protein-truncating mutations in BRCA2 and BRIP1 were discovered in African American men diagnosed with early-onset prostate cancer. Further study is necessary to determine the role of rare, missense variants to prostate cancer incidence, and progression in this group of high-risk men.
| S-EPMC6912854 | biostudies-literature