title: The pattern of congenital heart defects arising from reduced Tbx5 expression is altered in a Down syndrome mouse model.
abstract: BACKGROUND
  Nearly half of all individuals with Down Syndrome (DS) have some type of congenital heart defect (CHD), suggesting that DS sensitizes to CHD but does not cause it. We used a common mouse model of DS, the Ts65Dn mouse, to study the contribution of Tbx5, a known modifier of CHD, to heart defects on a trisomic backgroun. Mice that were heterozygous for a Tbx5 null allele were crossed with Ts65Dn mice. Thoraxes of progeny were fixed in 10% formalin, embedded in paraffin, and sectioned for analysis of CHD. Gene expression in embryonic hearts was examined by quantitative PCR and in situ hybridization. A TBX5 DNA binding site was verified by luciferase assays.
  
  
  METHODS
  Mice that were heterozygous for a Tbx5 null allele were crossed with Ts65Dn mice. Thoraxes of progeny were fixed in 10% formalin, embedded in paraffin, and sectioned for analysis of CHD. Gene expression in embryonic hearts was examined by quantitative PCR and in situ hybridization. A TBX5 DNA binding site was verified by luciferase assays.
  
  
  RESULTS
  We crossed mice that were heterozygous for a Tbx5 null allele with Ts65Dn mice. Mice that were trisomic and carried the Tbx5 mutation (Ts65Dn;Tbx5 (+/-) ) had a significantly increased incidence of overriding aorta compared to their euploid littermates. Ts65Dn;Tbx5 (+/-) mice also showed reduced expression of Pitx2, a molecular marker for the left atrium. Transcript levels of the trisomic Adamts1 gene were decreased in Tbx5 (+/-) mice compared to their euploid littermates. Evidence of a valid binding site for TBX5 upstream of the trisomic Adamts1 locus was also shown.
  
  
  CONCLUSIONS
  Haploinsufficiency of Tbx5 and trisomy affects alignment of the aorta and this effect may stem from deviations from normal left-right patterning in the heart. We have unveiled a previously unknown interaction between the Tbx5 gene and trisomy, suggesting a connection between Tbx5 and trisomic genes important during heart development.
authors.affiliation: Department of Physiology at Johns Hopkins, Biophysics 201, 725 N. Wolfe St., Baltimore, MD, 21205, USA.|McKusick Nathans Institute for Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Renita C
authors.initials: RC
authors.lastname: Polk
authors.affiliation: Department of Human Genetics, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Gergics
authors.affiliation: Departments of Pediatrics, Pathology and Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Steimle
authors.affiliation: Department of Physiology at Johns Hopkins, Biophysics 201, 725 N. Wolfe St., Baltimore, MD, 21205, USA.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Li
authors.affiliation: Departments of Pediatrics, Pathology and Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Moskowitz
authors.affiliation: Department of Human Genetics, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Camper
authors.affiliation: Department of Physiology at Johns Hopkins, Biophysics 201, 725 N. Wolfe St., Baltimore, MD, 21205, USA. rreeves@jhmi.edu.|McKusick Nathans Institute for Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. rreeves@jhmi.edu.
authors.forename: Roger H
authors.initials: RH
authors.lastname: Reeves
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D018628:Gene Dosage; D006330:Heart Defects, Congenital / Q000235:genetics*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D014314:Trisomy
chemical_list: D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5