Is there a role for rare variants in DRD4 gene in the susceptibility for ADHD Searching for an effect of allelic heterogeneity
- Authors: Tovo-Rodrigues, Luciana , Rohde, Luis , Roman, Tatiana , Schmitz, Marcelo , Polanczyk, Guilherme , Zeni, Cristian , Marques, Francine , Contini, Veronica , Grevet, Eugenio , Belmonte-De-Abreu, Paulo , Bau, Claiton , Hutz, Mara
- Date: 2012
- Type: Text , Journal article
- Relation: Molecular Psychiatry Vol. 17, no. 5 (May 2012), p. 520-526
- Full Text: false
- Reviewed:
- Description: Although several studies have demonstrated an association between the 7-repeat (7R) allele in the 48-bp variable number of tandem repeats (VNTRs) in the exon 3 at dopamine receptor D4 (DRD4) gene and attention-deficit/ hyperactivity disorder (ADHD), others failed to replicate this finding. In this study, a total of 786 individuals with ADHD were genotyped for DRD4 exon 3 VNTR. All 7R homozygous subjects were selected for VNTR re-sequencing. Subjects homozygous for the 4R allele were selected paired by age, ancestry and disorder subtypes in order to have a sample as homogeneous as possible with 7R/7R individuals. Using these criteria, 103 individuals (66 with ADHD and 37 control individuals) were further investigated. An excess of rare variants were observed in the 7R alleles of ADHD patient when compared with controls (P = 0.031). This difference was not observed in 4R allele. Furthermore, nucleotide changes that predict synonymous and non-synonymous substitutions were more common in the 7R sample (P = 0.008 for total substitutions and P = 0.043 for non-synonymous substitutions). In silico prediction of structural/functional alterations caused by these variants have also been observed. Our findings suggest that not only repeat length but also DNA sequence should be assessed to better understand the role of DRD4 exon 3 VNTR in ADHD genetic susceptibility.
- Description: C1
β-Adrenergic signaling regulates NR4A nuclear receptor and metabolic gene expression in multiple tissues
- Authors: Myers, Stephen , Eriksson, Natalie , Burow, Rachel , Wang, Mary Shu-Ching , Muscat, George
- Date: 2009
- Type: Text , Journal article
- Relation: Molecular and Cellular Endocrinology Vol. 309, no. 1-2 (2009), p. 101-108
- Full Text: false
- Reviewed:
- Description: The nuclear hormone receptor (NR) 4A subgroup of orphan nuclear receptors includes three members, Nur77 (NR4A1), Nurr1 (NR4A2) and Nor-1 (NR4A3). Previously we have identified the rapid and robust (in vitro and in vivo) induction of the NR4A subgroup following β-adrenergic stimulation in mouse skeletal muscle. This was concomitant with changes in the expression of genes involved in the regulation of nutrient metabolism. We have isolated mouse tissue of cardiovascular, endocrine and gastrointestinal origin at 1, 4, 8 and 24 h after a single intraperitoneal injection of the β-adrenergic agonist, isoprenaline. We similarly identified the significant induction (between 1 and 4 h) of the NR4A genes in many of these tissues. Moreover, we have utilized TaqMan ® Low Density Arrays to determine the β-adrenergic-sensitive metabolic gene expression in liver, white adipose and heart. In summary, cross-talk between β-adrenergic and NR4A signaling occurs in several tissues, and is accompanied by modulation of metabolic gene expression. © 2009 Elsevier Ireland Ltd. All rights reserved.
The NF-κB1 transcription factor prevents the intrathymic development of CD8 T cells with memory properties
- Authors: Gugasyan, Raffi , Horat, Elisha , Kinkel, Sarah , Ross, Fiona , Grigoriadis, George , Gray, Daniel , O'Keeffe, Meredith , Berzins, Stuart , Belz, Gabrielle , Grumont, Raelene , Banerjee, Ashish , Strasser, Andreas , Godfrey, Dale , Tsichlis, Phillip , Gerondakis, Steve
- Date: 2012
- Type: Text , Journal article
- Relation: EMBO Journal Vol. 31, no. 3 (2012), p. 692-706
- Full Text: false
- Reviewed:
- Description: The role of specific members of the NF-κB family of transcription factors in CD8 T-cell selection and development is largely unknown. Here, we show that mice lacking NF-κB1 develop a unique population of conventional CD8 single-positive (SP) thymocytes with memory T cell-like properties that populate peripheral immune organs. Development of this memory-like population is not due to PLZF + thymocytes and instead coincides with changes in CD8 T-cell selection. These include a reduction in the efficiency of negative selection and a dependence on MHC class Ia or Ib expressed by haematopoietic cells. These findings indicate that NF-κB1 regulates multiple events in the thymus that collectively inhibit the excess development of CD8 + thymocytes with memory cell characteristics. © 2012 European Molecular Biology Organization | All Rights Reserved.