Dataset Information

Disorders with similar clinical phenotypes reveal underlying genetic interaction: SATB2 acts as an activator of the UPF3B gene.

ABSTRACT: Two syndromic cognitive impairment disorders have very similar craniofacial dysmorphisms. One is caused by mutations of SATB2, a transcription regulator and the other by heterozygous mutations leading to premature stop codons in UPF3B, encoding a member of the nonsense-mediated mRNA decay complex. Here we demonstrate that the products of these two causative genes function in the same pathway. We show that the SATB2 nonsense mutation in our patient leads to a truncated protein that localizes to the nucleus, forms a dimer with wild-type SATB2 and interferes with its normal activity. This suggests that the SATB2 nonsense mutation has a dominant negative effect. The patient's leukocytes had significantly decreased UPF3B mRNA compared to controls. This effect was replicated both in vitro, where siRNA knockdown of SATB2 in HEK293 cells resulted in decreased UPF3B expression, and in vivo, where embryonic tissue of Satb2 knockout mice showed significantly decreased Upf3b expression. Furthermore, chromatin immunoprecipitation demonstrates that SATB2 binds to the UPF3B promoter, and a luciferase reporter assay confirmed that SATB2 expression significantly activates gene transcription using the UPF3B promoter. These findings indicate that SATB2 activates UPF3B expression through binding to its promoter. This study emphasizes the value of recognizing disorders with similar clinical phenotypes to explore underlying mechanisms of genetic interaction.

SUBMITTER: Leoyklang P

PROVIDER: S-EPMC4160176 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Disorders with similar clinical phenotypes reveal underlying genetic interaction: SATB2 acts as an activator of the UPF3B gene.

Leoyklang Petcharat P Suphapeetiporn Kanya K Srichomthong Chalurmpon C Tongkobpetch Siraprapa S Fietze Stefanie S Dorward Heidi H Cullinane Andrew R AR Gahl William A WA Huizing Marjan M Shotelersuk Vorasuk V

Human genetics 20130808 12

Two syndromic cognitive impairment disorders have very similar craniofacial dysmorphisms. One is caused by mutations of SATB2, a transcription regulator and the other by heterozygous mutations leading to premature stop codons in UPF3B, encoding a member of the nonsense-mediated mRNA decay complex. Here we demonstrate that the products of these two causative genes function in the same pathway. We show that the SATB2 nonsense mutation in our patient leads to a truncated protein that localizes to t ...[more]

PMID: 23925499

Similar Datasets

Project description:IntroductionClinical guidelines state that disseminated intravascular coagulation (DIC) treatment should be based on three clinical phenotypes: the marked bleeding type (e.g. leukemia, trauma, obstetric diseases, or aortic diseases); organ failure type (sepsis or pancreatitis); and asymptomatic type of DIC (solid cancer). However, among the various underlying disorders of DIC, the clinical presentations of bleeding or organ failure have not to date been well documented. The present study aimed to evaluate whether underlying disorders of DIC would affect clinical outcome including death, organ failure, and bleeding.MethodsUsing the Japanese Diagnosis Procedure Combination inpatient database, we identified all adult patients diagnosed with DIC during hospitalization from July 1, 2010, to March 31, 2018. We collected data on patient characteristics and underlying disorders of DIC including sepsis, solid cancer, leukemia, trauma, obstetric diseases, aortic diseases, pancreatitis, and miscellaneous diseases. We counted major bleeding events and calculated an organ failure score for patients during hospitalization.ResultsWe identified 337,132 patients with DIC. The major disorders underlying DIC were sepsis (42%) and solid cancer (31%). The average organ failure scores of patients with aortic diseases, sepsis, and trauma were 2.8, 2.2, and 2.2, respectively. The percentages with major bleeding events among patients with aortic diseases, trauma, obstetric diseases, and solid cancer were 24%, 15%, 10%, and 10%, respectively.ConclusionsThis study suggests that the clinical presentations of bleeding and organ failure are not associated with the three existing clinical phenotypes of DIC or with the underlying disorders of DIC. Therefore, clinical presentation alone may not be sufficient for identifying the clinical phenotypes of DIC. Further research is necessary to develop new strategies for identifying the phenotypes of DIC and improving treatment strategies for individual patients.

Project description:BACKGROUND:Common metabolic diseases, including type 2 diabetes, coronary artery disease, and hypertension, arise from disruptions of the body's metabolic homeostasis, with relatively strong contributions from genetic risk factors and substantial comorbidity with obesity. Although genome-wide association studies have revealed many genomic loci robustly associated with these diseases, biological interpretation of such association is challenging because of the difficulty in mapping single-nucleotide polymorphisms (SNPs) onto the underlying causal genes and pathways. Furthermore, common diseases are typically highly polygenic, and conventional single variant-based association testing does not adequately capture potentially important large-scale interaction effects between multiple genetic factors. METHODS:We analyzed moderately sized case-control data sets for type 2 diabetes, coronary artery disease, and hypertension to characterize the genetic risk factors arising from non-additive, collective interaction effects, using a recently developed algorithm (discrete discriminant analysis). We tested associations of genes and pathways with the disease status while including the cumulative sum of interaction effects between all variants contained in each group. RESULTS:In contrast to non-interacting SNP mapping, which produced few genome-wide significant loci, our analysis revealed extensive arrays of pathways, many of which are involved in the pathogenesis of these metabolic diseases but have not been directly identified in genetic association studies. They comprised cell stress and apoptotic pathways for insulin-producing ?-cells in type 2 diabetes, processes covering different atherosclerotic stages in coronary artery disease, and elements of both type 2 diabetes and coronary artery disease risk factors (cell cycle, apoptosis, and hemostasis) associated with hypertension. CONCLUSIONS:Our results support the view that non-additive interaction effects significantly enhance the level of common metabolic disease associations and modify their genetic architectures and that many of the expected genetic factors behind metabolic disease risks reside in smaller genotyping samples in the form of interacting groups of SNPs.

Project description:The proteasome inhibitor MG132 had been shown to prevent galactose induction of the S. cerevisiae GAL1 gene, demonstrating that ubiquitin proteasome-dependent degradation of transcription factors plays an important role in the regulation of gene expression. The deletion of the gene encoding the F-box protein Mdm30 had been reported to stabilize the transcriptional activator Gal4 under inducing conditions and to lead to defects in galactose utilization, suggesting that recycling of Gal4 is required for its function. Subsequently, however, it was argued that Gal4 remains stably bound to the enhancer under inducing conditions, suggesting that proteolytic turnover of Gal4 might not be required for its function. We have performed an alanine-scanning mutagenesis of ubiquitin and isolated a galactose utilization-defective ubiquitin mutant. We have used it for an unbiased suppressor screen and identified the inhibitor Gal80 as a suppressor of the transcriptional defects of the ubiquitin mutant, indicating that the protein degradation of the inhibitor Gal80, and not of the activator Gal4, is required for galactose induction of the GAL genes. We also show that in the absence of Gal80, Mdm30 is not required for Gal4 function, strongly supporting this hypothesis. Furthermore, we have found that Mediator controls the galactose-induced protein degradation of Gal80, which places Mediator genetically upstream of the activator Gal4. Mediator had originally been isolated by its ability to respond to transcriptional activators, and here we have discovered a leading role for Mediator in the process of transcription. The protein kinase Snf1 senses the inducing conditions and transduces the signal to Mediator, which initiates the degradation of the inhibitor Gal80 with the help of the E3 ubiquitin ligase SCF(Mdm30). The ability of Mediator to control the protein degradation of transcriptional inhibitors indicates that Mediator is actually able to direct its own recruitment to gene promoters.

Dataset Information

Disorders with similar clinical phenotypes reveal underlying genetic interaction: SATB2 acts as an activator of the UPF3B gene.

Publications

Disorders with similar clinical phenotypes reveal underlying genetic interaction: SATB2 acts as an activator of the UPF3B gene.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets