1. NRP1 haploinsufficiency predisposes to the development of Tetralogy of Fallot
- Author
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Duran, Ivan, Tenney, Jessica, Warren, Carmen M, Sarukhanov, Anna, Csukasi, Fabiana, Skalansky, Mark, Iruela‐Arispe, Maria L, and Krakow, Deborah
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Heart Disease ,Genetics ,Cardiovascular ,1.1 Normal biological development and functioning ,Underpinning research ,2.1 Biological and endogenous factors ,Aetiology ,Biomarkers ,Comparative Genomic Hybridization ,DNA Mutational Analysis ,Endothelial Cells ,Gene Expression ,Genetic Association Studies ,Genetic Predisposition to Disease ,Genotype ,Haploinsufficiency ,Humans ,Neuropilin-1 ,Pedigree ,Phenotype ,Polymorphism ,Single Nucleotide ,Sequence Analysis ,DNA ,Tetralogy of Fallot ,Ultrasonography ,chromosomal deletion ,congenital heart disease ,neuropilin 1 ,prenatal ultrasound ,tetralogy of fallot ,Clinical Sciences ,Clinical sciences - Abstract
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.
- Published
- 2018