Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease

Kryn Stankunas, Ching Shang, Karen Y. Twu, Shih Chu Kao, Nancy A. Jenkins, Neal G. Copeland, Mrinmoy Sanyal, Licia Selleri, Michael L. Cleary, Ching Pin Chang

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Congenital heart diseases are traditionally considered to be multifactorial in pathogenesis resulting from environmental and genetic interactions that determine penetrance and expressivity within a genetically predisposed family. Recent evidence suggests that genetic contributions have been significantly underestimated. However, single gene defects occur only in a minority of cases, and multigenetic causes of congenital heart diseases have not been fully demonstrated. Here, we show that interactions between alleles of 3 Pbx genes, which encode homeodomain transcription factors, are sufficient to determine the phenotypic presentation of congenital heart diseases in mice. A major role is served by Pbx1, whose inactivation results in persistent truncus arteriosus. Reduction or absence of Pbx2 or Pbx3 leads to Pbx1 haploinsufficiency and specific malformations that resemble tetralogy of Fallot, overriding aorta with ventricular septal defect, and bicuspid aortic valves. Disruption of Meis1, which encodes a Pbx DNA-binding partner, results in cardiac anomalies that resemble those caused by Pbx mutations. Each of the observed cardiac defects represents developmental abnormalities affecting distinct stages of cardiac outflow tract development and corresponds to specific types of human congenital heart disease. Thus, varied deficiencies in the Pbx gene family produce a full spectrum of cardiac defects involving the outflow tract, providing a framework for determining multigenetic causes of congenital heart anomalies.

Original languageEnglish (US)
Pages (from-to)702-709
Number of pages8
JournalCirculation research
Volume103
Issue number7
DOIs
StatePublished - Sep 26 2008

Fingerprint

Heart Diseases
Persistent Truncus Arteriosus
Haploinsufficiency
Inborn Genetic Diseases
Tetralogy of Fallot
Penetrance
Ventricular Heart Septal Defects
Genes
Aorta
Transcription Factors
Alleles
Mutation
DNA

Keywords

  • Congenital heart disease
  • Heart development
  • Hox
  • Meis
  • Pbx

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Stankunas, K., Shang, C., Twu, K. Y., Kao, S. C., Jenkins, N. A., Copeland, N. G., ... Chang, C. P. (2008). Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease. Circulation research, 103(7), 702-709. https://doi.org/10.1161/CIRCRESAHA.108.175489

Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease. / Stankunas, Kryn; Shang, Ching; Twu, Karen Y.; Kao, Shih Chu; Jenkins, Nancy A.; Copeland, Neal G.; Sanyal, Mrinmoy; Selleri, Licia; Cleary, Michael L.; Chang, Ching Pin.

In: Circulation research, Vol. 103, No. 7, 26.09.2008, p. 702-709.

Research output: Contribution to journalArticle

Stankunas, K, Shang, C, Twu, KY, Kao, SC, Jenkins, NA, Copeland, NG, Sanyal, M, Selleri, L, Cleary, ML & Chang, CP 2008, 'Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease', Circulation research, vol. 103, no. 7, pp. 702-709. https://doi.org/10.1161/CIRCRESAHA.108.175489
Stankunas K, Shang C, Twu KY, Kao SC, Jenkins NA, Copeland NG et al. Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease. Circulation research. 2008 Sep 26;103(7):702-709. https://doi.org/10.1161/CIRCRESAHA.108.175489
Stankunas, Kryn ; Shang, Ching ; Twu, Karen Y. ; Kao, Shih Chu ; Jenkins, Nancy A. ; Copeland, Neal G. ; Sanyal, Mrinmoy ; Selleri, Licia ; Cleary, Michael L. ; Chang, Ching Pin. / Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease. In: Circulation research. 2008 ; Vol. 103, No. 7. pp. 702-709.
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