Dysregulation of the PDGFRA gene causes inflow tract anomalies including TAPVR: Integrating evidence from human genetics and model organisms

Steven B. Bleyl, Yukio Saijoh, Noortje A.M. Bax, Adriana C. Gittenberger-de Groot, Lambertus J. Wisse, Susan C. Chapman, Jennifer Hunter, Hidetaka Shiratori, Hiroshi Hamada, Shigehito Yamada, Kohei Shiota, Scott E. Klewer, Mark F. Leppert, Gary C. Schoenwolf

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Total anomalous pulmonary venous return (TAPVR) is a congenital heart defect inherited via complex genetic and/or environmental factors. We report detailed mapping in extended TAPVR kindreds and mutation analysis in TAPVR patients that implicate the PDGFRA gene in the development of TAPVR. Gene expression studies in mouse and chick embryos for both the Pdgfra receptor and its ligand Pdgf-a show temporal and spatial patterns consistent with a role in pulmonary vein (PV) development. We used an in ovo function blocking assay in chick and a conditional knockout approach inmouse to knock down Pdgfra expression in the developing venous pole during the period of PV formation.We observed that loss of PDGFRA function in both organisms causes TAPVR with lowpenetrance (~7%) reminiscent of that observed in ourhumanTAPVRkindreds. Intermediate inflowtract anomalies occurred in a higher percentage of embryos (~30%), suggesting that TAPVR occurs at one end of a spectrum of defects. We show that the anomalous pulmonary venous connection seen in chick and mouse is highly similar to TAPVR discovered in an abnormal early stage embryo fromthe Kyoto human embryo collection. Whereas the embryology of the normal venous pole and PV is becoming understood, little is known about the embryogenesis or molecular pathogenesis of TAPVR. These models of TAPVR provide important insight into the pathogenesis of PV defects. Taken together, these data from human genetics and animal models support a role for PDGF-signaling in normal PV development, and in the pathogenesis of TAPVR.

Original languageEnglish (US)
Article numberddq005
Pages (from-to)1286-1301
Number of pages16
JournalHuman molecular genetics
Issue number7
StatePublished - Jan 13 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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