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      Novel Mutations in the Transcriptional Activator Domain of the Human TBX20 in Patients with Atrial Septal Defect

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          Abstract

          Background. The relevance of TBX20 gene in heart development has been demonstrated in many animal models, but there are few works that try to elucidate the effect of TBX20 mutations in human congenital heart diseases. In these studies, all missense mutations associated with atrial septal defect (ASD) were found in the DNA-binding T-box domain, none in the transcriptional activator domain. Methods. We search for TBX20 mutations in a group of patients with ASD or ventricular septal defect (VSD) using the High Resolution Melting (HRM) method and DNA sequencing. Results. We report three missense mutations (Y309D, T370O, and M395R) within the transcriptional activator domain of human TBX20 that were associated with ASD. Conclusions. This is the first association of TBX20 transcriptional activator domain missense mutations with ASD. These findings could have implications for diagnosis, genetic screening, and patient follow-up.

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          Congenital heart disease in the general population: changing prevalence and age distribution.

          Ariane J Marelli, Andrew S Mackie, Raluca Ionescu-Ittu … (2007)
          Empirical data on the changing epidemiology of congenital heart disease (CHD) are scant. We determined the prevalence, age distribution, and proportion of adults and children with severe and other forms of CHD in the general population from 1985 to 2000. Where healthcare access is universal, we used administrative databases that systematically recorded all diagnoses and claims. Diagnostic codes conformed to the International Classification of Disease, ninth revision. Severe CHD was defined as tetralogy of Fallot, truncus arteriosus, transposition complexes, endocardial cushion defects, and univentricular heart. Prevalence of severe and other CHD lesions was determined in 1985, 1990, 1995, and 2000 using population numbers in Quebec. Children were subjects <18 years of age. The prevalence was 4.09 per 1000 adults in the year 2000 for all CHD and 0.38 per 1000 (9%) for those with severe lesions. Female subjects accounted for 57% of the adult CHD population. The median age of all patients with severe CHD was 11 years (interquartile range, 4 to 22 years) in 1985 and 17 years (interquartile range, 10 to 28 years) in 2000 (P<0.0001). The prevalence of severe CHD increased from 1985 to 2000, but the increase in adults was significantly higher than that observed in children. In the year 2000, 49% of those alive with severe CHD were adults. The prevalence in adults and median age of patients with severe CHD increased in the general population from 1985 to 2000. In 2000, there were nearly equal numbers of adults and children with severe CHD.
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            Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function.

            Scott Smemo, Fang-Ju Chen, Fred C. Boogerd … (2011)
            Human mutations in or variants of TBX20 are associated with congenital heart disease, cardiomyopathy, and arrhythmias. To investigate whether cardiac disease in patients with these conditions results from an embryonic or ongoing requirement for Tbx20 in myocardium, we ablated Tbx20 specifically in adult cardiomyocytes in mice. This ablation resulted in the onset of severe cardiomyopathy accompanied by arrhythmias, with death ensuing within 1 to 2 weeks of Tbx20 ablation. Accounting for this dramatic phenotype, we identified molecular signatures that posit Tbx20 as a central integrator of a genetic program that maintains cardiomyocyte function in the adult heart. Expression of a number of genes encoding critical transcription factors, ion channels, and cytoskeletal/myofibrillar proteins was downregulated consequent to loss of Tbx20. Genome-wide ChIP analysis of Tbx20-binding regions in the adult heart revealed that many of these genes were direct downstream targets of Tbx20 and uncovered a previously undescribed DNA-binding site for Tbx20. Bioinformatics and in vivo functional analyses revealed a cohort of transcription factors that, working with Tbx20, integrated multiple environmental signals to maintain ion channel gene expression in the adult heart. Our data provide insight into the mechanisms by which mutations in TBX20 cause adult heart disease in humans.
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              Crystallographic structure of the T domain-DNA complex of the Brachyury transcription factor.

              Christoph Müller, B Herrmann (1997)
              The mouse Brachyury (T) gene is the prototype of a growing family of so-called T-box genes which encode transcriptional regulators and have been identified in a variety of invertebrates and vertebrates, including humans. Mutations in Brachyury and other T-box genes result in drastic embryonic phenotypes, indicating that T-box gene products are essential in tissue specification, morphogenesis and organogenesis. The T-box encodes a DNA-binding domain of about 180 amino-acid residues, the T domain. Here we report the X-ray structure of the T domain from Xenopus laevis in complex with a 24-nucleotide palindromic DNA duplex. We show that the protein is bound as a dimer, interacting with the major and the minor grooves of the DNA. A new type of specific DNA contact is seen, in which a carboxy-terminal helix is deeply embedded into an enlarged minor groove without bending the DNA. Hydrophobic interactions and an unusual main-chain carbonyl contact to a guanine account for sequence-specific recognition in the minor groove by this helix. Thus the structure of this T domain complex with DNA reveals a new way in which a protein can recognize DNA.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biomed Res Int
                Journal ID (iso-abbrev): Biomed Res Int
                Journal ID (publisher-id): BMRI
                Title: BioMed Research International
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 2314-6133
                ISSN (Electronic): 2314-6141
                Publication date (Print): 2015
                Publication date (Electronic): 5 March 2015
                Volume: 2015
                Electronic Location Identifier: 718786
                Affiliations
                1Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, 14080 Mexico City, Mexico
                2Central Laboratory of Epidemiology, Instituto Mexicano del Seguro Social, 02900 Mexico City, Mexico
                3Department of Biology, Chemistry Faculty, Universidad Nacional Autónoma de México, 04510 Mexico City, Mexico
                4Department of Physiology, Instituto Nacional de Cardiología Ignacio Chávez, 14080 Mexico City, Mexico
                5Department of Pediatric Cardiology, Instituto Nacional de Cardiología Ignacio Chávez, 14080 Mexico City, Mexico
                6Department of Congenital Heart Disease Surgery, Department of Pediatric Cardiology, Instituto Nacional de Cardiología Ignacio Chávez, 14080 Mexico City, Mexico
                7Department of Interventional Cardiology, Instituto Nacional de Cardiología Ignacio Chávez, 14080 Mexico City, Mexico
                Author notes
                *Gilberto Vargas-Alarcón: gvargas63@ 123456yahoo.com

                Academic Editor: María E. Esteban

                Author information
                http://orcid.org/0000-0003-4786-508X
                Article
                DOI: 10.1155/2015/718786
                PMC ID: 4365367
                PubMed ID: 25834824
                SO-VID: 12809d41-c73b-48d0-9ab6-8c1fb9619102
                Copyright © Copyright © 2015 Irma Eloisa Monroy-Muñoz et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 15 August 2014
                Date accepted : 20 October 2014
                Categories
                Subject: Research Article

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