Congenital heart defects (CHDs) are the most common developmental anomaly and are the leading non-infectious cause of mortality in newborns. Only one causative gene, NKX2-5, has been identified through genetic linkage analysis of pedigrees with non-syndromic CHDs. Here, we show that isolated cardiac septal defects in a large pedigree were linked to chromosome 8p22-23. A heterozygous G296S missense mutation of GATA4, a transcription factor essential for heart formation, was found in all available affected family members but not in any control individuals. This mutation resulted in diminished DNA-binding affinity and transcriptional activity of Gata4. Furthermore, the Gata4 mutation abrogated a physical interaction between Gata4 and TBX5, a T-box protein responsible for a subset of syndromic cardiac septal defects. Conversely, interaction of Gata4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. In a second family, we identified a frame-shift mutation of GATA4 (E359del) that was transcriptionally inactive and segregated with cardiac septal defects. These results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5.
A yeast two-hybrid assay was employed to identify androgen receptor (AR) protein partners in gonadotropin-releasing hormone neuronal cells. By using an AR deletion construct (AR-(⌬371-485)) as a bait, -catenin was identified as an AR-interacting protein from a gonadotropin-releasing hormone neuronal cell library. Immunolocalization of co-transfected AR and FLAG--catenin demonstrated that FLAG--catenin was predominantly cytoplasmic in the absence of androgen. In the presence of 5␣-dihydrotestosterone, FLAG--catenin completely co-localized to the nucleus with AR. This effect was specific to AR because liganded progesterone, glucocorticoid, or estrogen ␣ receptors did not translocate FLAG--catenin to the nucleus. Agonist-bound AR was required because the AR antagonists casodex and hydroxyflutamide failed to translocate -catenin. Time course experiments demonstrated that co-translocation occurred with similar kinetics. Nuclear co-localization was independent of the glycogen synthase kinase-3, p42/44 ERK mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways because inhibitors of these pathways had no effect. Transcription assays demonstrated that liganded AR repressed -catenin/T cell factor-responsive reporter gene activity. Conversely, co-expression of -catenin/T cell factor repressed AR stimulation of AR-responsive reporter gene activity. Our data suggest that liganded AR shuttles -catenin to the nucleus and that nuclear interaction of AR with -catenin may modulate transcriptional activity in androgen target tissues.
This study suggests the SP has acceptable test-retest reliability and internal consistency and supports the use of quadrant scores over factor and section scores to analyze children's sensory processing patterns.
There are two separate estrogen receptors (ERs), ERalpha and ERbeta. The ERbeta gene is variably spliced, and in some cases variant expression is high. Besides the full-length ERbeta (equivalent to ERbeta1), splice variants can encode proteins bearing an insert within the ligand-binding domain (beta2), a deletion of exon 3 (ERbeta1delta3) disrupting the DNA-binding domain, or both (ERbeta2delta3). Here we examine the intracellular localization and transcriptional properties of each of the ERbeta splice variants heterologously expressed in cultured cells. In accordance with ERalpha, ERbeta1 and ERbeta2 are both distributed in a reticular pattern within the nucleus after exposure to ligand. In contrast, ERbeta1delta3 and ERbeta2delta3 localize to discrete spots within the nucleus in the presence of ER agonists. In the presence of ER antagonists, the delta3 variants are distributed diffusely within the nucleus. We also show that the spots are stable nuclear structures to which the delta3 variants localize in a ligand-dependent manner. Coactivator proteins of ER colocalize with delta3 variants in the spots in the presence of agonists. The delta3 variants of ERbeta can activate luciferase reporter constructs containing an activator protein complex-1 site, but not an estrogen response element (ERE). These data suggest that without an intact DNA-binding domain, ERbeta is functionally altered, allowing localization to discrete nuclear spots and activation from activator protein-1-containing reporter genes.
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