Allelic Interaction between CRELD1 and VEGFA in the Pathogenesis of Cardiac Atrioventricular Septal Defects

Jennifer K. Redig; Gameil T. Fouad; Darcie Babcock; Benjamin Reshey; Eleanor Feingold; Roger H. Reeves; Cheryl L. Maslen

doi:10.3934/genet.2014.1.1

AIMS Genetics, Table of Contents

CC BY 4.0 · AIMS Genet 2014; 01(01): 001-019
DOI: 10.3934/genet.2014.1.1

Research Article

Allelic Interaction between CRELD1 and VEGFA in the Pathogenesis of Cardiac Atrioventricular Septal Defects

Authors

Jennifer K. Redig

¹Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA

²Current address, Hume Center for Writing and Speaking, Stanford University, Stanford, CA 94305, USA
Gameil T. Fouad

¹Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA

³Current address, Biotron Laboratories, West Centerville, UT 84014, USA
Darcie Babcock

⁴Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97239, USA
Benjamin Reshey

⁵Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA
Eleanor Feingold

⁶Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh PA 15261, USA
Roger H. Reeves

⁷Department of Physiology and the Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Cheryl L. Maslen

¹Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA

⁵Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA

Abstract

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Abstract

Atrioventricular septal defects (AVSD) are highly heritable, clinically significant congenital heart malformations. Genetic and environmental modifiers of risk are thought to work in unknown combinations to cause AVSD. Approximately 5–10% of simplex AVSD cases carry a missense mutation in CRELD1. However, CRELD1 mutations are not fully penetrant and require interactions with other risk factors to result in AVSD. Vascular endothelial growth factor-A (VEGFA) is a well-characterized modulator of heart valve development. A functional VEGFA polymorphism, VEGFA c.−634C, which causes constitutively increased VEGFA expression, has been associated with cardiac septal defects suggesting it may be a genetic risk factor. To determine if there is an allelic association with AVSD we genotyped the VEGFA c.−634 SNP in a simplex AVSD study cohort. Over-representation of the c.−634C allele in the AVSD group suggested that this genotype may increase risk. Correlation of CRELD1 and VEGFA genotypes revealed that potentially pathogenic missense mutations in CRELD1 were always accompanied by the VEGFA c.−634C allele in individuals with AVSD suggesting a potentially pathogenic allelic interaction. We used a Creld1 knockout mouse model to determine the effect of deficiency of Creld1 combined with increased VEGFA on atrioventricular canal development. Morphogenic response to VEGFA was abnormal in Creld1-deficient embryonic hearts, indicating that interaction between CRELD1 and VEGFA has the potential to alter atrioventricular canal morphogenesis. This supports our hypothesis that an additive effect between missense mutations in CRELD1 and a functional SNP in VEGFA contributes to the pathogenesis of AVSD.

Keywords

congenital heart disease - genetic modifier

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