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NRP1 haploinsufficiency predisposes to the development of Tetralogy of Fallot
Author(s) -
Duran Ivan,
Tenney Jessica,
Warren Carmen M.,
Sarukhanov Anna,
Csukasi Fabiana,
Skalansky Mark,
IruelaArispe Maria L.,
Krakow Deborah
Publication year - 2018
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.38600
Subject(s) - tetralogy of fallot , neuropilin 1 , haploinsufficiency , medicine , omim : online mendelian inheritance in man , biology , heart disease , endocrinology , cardiology , genetics , gene , vascular endothelial growth factor , vegf receptors , phenotype
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect. It involves anatomical abnormalities that change the normal flow of blood through the heart resulting in low oxygenation. Although not all of the underlying causes of TOF are completely understood, the disease has been associated with varying genetic etiologies including chromosomal abnormalities and Mendelian disorders, but can also occur as an isolated defect. In this report, we describe a familial case of TOF associated with a 1.8 Mb deletion of chromosome 10p11. Among the three genes in the region one is Neuropilin1 (NRP1) , a membrane co‐receptor of VEGF that modulates vasculogenesis. Hemizygous levels of NRP1 resulted in a reduced expression at the transcriptional and protein levels in patient‐derived cells. Reduction of NRP1 also lead to decreased function of its activity as a co‐receptor in intermolecular VEGF signaling. These findings support that diminished levels of NRP1 contribute to the development of TOF, likely through its function in mediating VEGF signal and vasculogenesis.