Tbx5-dependent pathway regulating diastolic function in congenital heart disease

Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5519-24. doi: 10.1073/pnas.0801779105. Epub 2008 Mar 31.


At the end of every heartbeat, cardiac myocytes must relax to allow filling of the heart. Impaired relaxation is a significant factor in heart failure, but all pathways regulating the cardiac relaxation apparatus are not known. Haploinsufficiency of the T-box transcription factor Tbx5 in mouse and man causes congenital heart defects (CHDs) as part of Holt-Oram syndrome (HOS). Here, we show that haploinsufficiency of Tbx5 in mouse results in cell-autonomous defects in ventricular relaxation. Tbx5 dosage modulates expression of the sarco(endo)plasmic reticulum Ca(2+)-ATPase isoform 2a encoded by Atp2a2 and Tbx5 haploinsufficiency in ventricular myocytes results in impaired Ca(2+) uptake dynamics and Ca(2+) transient prolongation. We also demonstrate that Tbx5 can activate the Atp2a2 promoter. Furthermore, we find that patients with HOS have significant diastolic filling abnormalities. These results reveal a direct genetic pathway that regulates cardiac diastolic function, implying that patients with structural CHDs may have clinically important underlying anomalies in heart function that merit treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Case-Control Studies
  • Diastole / genetics*
  • Gene Expression Regulation / physiology
  • Heart Defects, Congenital / etiology*
  • Humans
  • Mice
  • Promoter Regions, Genetic
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics*
  • Signal Transduction
  • T-Box Domain Proteins / deficiency*
  • T-Box Domain Proteins / metabolism
  • T-Box Domain Proteins / physiology*


  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • ATP2A1 protein, human
  • Atp2a2 protein, mouse
  • Calcium