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

被引:47
作者
Bleyl, Steven B. [1 ,3 ]
Saijoh, Yukio [2 ,3 ]
Bax, Noortje A. M. [5 ]
Gittenberger-de Groot, Adriana C. [5 ]
Wisse, Lambertus J. [5 ]
Chapman, Susan C. [6 ]
Hunter, Jennifer [3 ]
Shiratori, Hidetaka [7 ]
Hamada, Hiroshi [7 ]
Yamada, Shigehito [8 ]
Shiota, Kohei [8 ]
Klewer, Scott E. [9 ]
Leppert, Mark F. [4 ]
Schoenwolf, Gary C. [3 ]
机构
[1] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT 84132 USA
[2] Univ Utah, Sch Med, Dept Human Mol Biol & Genet, Salt Lake City, UT 84132 USA
[3] Univ Utah, Sch Med, Dept Neurobiol & Anat, Salt Lake City, UT 84132 USA
[4] Univ Utah, Sch Med, Dept Human Genet, Salt Lake City, UT 84132 USA
[5] Leiden Univ, Med Ctr, Dept Anat & Embryol, NL-2300 RC Leiden, Netherlands
[6] Clemson Univ, Dept Biol Sci, Clemson, SC 29634 USA
[7] Osaka Univ, Dev Genet Grp, Grad Sch Frontier Biosci, Osaka, Japan
[8] Kyoto Univ, Dept Anat & Dev Biol, Grad Sch Med, Kyoto, Japan
[9] Univ Arizona, Coll Med, Div Pediat Cardiol, Dept Pediat, Tucson, AZ 85724 USA
基金
美国国家卫生研究院;
关键词
PULMONARY VENOUS RETURN; SINUS VENOSUS; CARDIAC DEVELOPMENT; ATRIAL SEPTUM; HUMAN EMBRYOS; HUMAN HEART; VEINS; MORPHOGENESIS; MYOCARDIUM; SEPTATION;
D O I
10.1093/hmg/ddq005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 in mouse 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 low penetrance (similar to 7%) reminiscent of that observed in our human TAPVR kindreds. Intermediate inflow tract anomalies occurred in a higher percentage of embryos (similar to 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 from the 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.
引用
收藏
页码:1286 / 1301
页数:16
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