Research article

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

  • Received: 01 February 2014 Accepted: 11 March 2014 Published: 27 March 2014
  • 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.

    Citation: Jennifer K. Redig, Gameil T. Fouad, Darcie Babcock, Benjamin Reshey, Eleanor Feingold, Roger H. Reeves, Cheryl L. Maslen. Allelic Interaction between CRELD1 and VEGFA in the Pathogenesis of Cardiac Atrioventricular Septal Defects[J]. AIMS Genetics, 2014, 1(1): 1-19. doi: 10.3934/genet.2014.1.1

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  • 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.
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    [1] Hoffman JIE, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39: 1890-1900. doi: 10.1016/S0735-1097(02)01886-7
    [2] Blue GM, Kirk EP, Sholler GF, et al. (2012) Congenital heart disease: current knowledge about causes and inheritance. Med J Aust 197: 155-159. doi: 10.5694/mja12.10811
    [3] Boening A, Scheewe J, Heine K, et al. (2002) Long-term results after surgical correction of atrioventricular septal defects. Eur J Cardiothorac Surg 22: 167-173. doi: 10.1016/S1010-7940(02)00272-5
    [4] Stulak JM, Burkhart HM, Dearani JA, et al. (2010) Reoperations after repair of partial atrioventricular septal defect: a 45-year single-center experience. Annals of Thoracic Surgery 89: 1352-1359. doi: 10.1016/j.athoracsur.2010.01.018
    [5] Ackerman C, Locke AE, Feingold E, et al. (2012) An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects. Am J Hum Genet 91: 646-659.
    [6] Maslen CL, Babcock D, Robinson SW, et al. (2006) CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down syndrome. Am J Med Genet A 140: 2501-2505.
    [7] Robinson SW, Morris CD, Goldmuntz E, et al. (2003) Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. American Journal of Human Genetics 72: 1047-1052. doi: 10.1086/374319
    [8] Li H, Cherry S, Klinedinst D, et al. (2012) Genetic Modifiers Predisposing to Congenital Heart Disease in the Sensitized Down Syndrome Population. Circ Cardiovasc Genet 5: 301-308. doi: 10.1161/CIRCGENETICS.111.960872
    [9] de Vlaming A, Sauls K, Hajdu Z, et al. (2012) Atrioventricular valve development: new perspectives on an old theme. Differentiation 84: 103-116. doi: 10.1016/j.diff.2012.04.001
    [10] Snarr BS, Wirrig EE, Phelps AL, et al. (2007) A spatiotemporal evaluation of the contribution of the dorsal mesenchymal protrusion to cardiac development. Dev Dyn 236: 1287-1294. doi: 10.1002/dvdy.21074
    [11] Dor Y, Camenisch TD, Itin A, et al. (2001) A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects. Development 128: 1531-1538.
    [12] Dor Y, Klewer SE, McDonald JA, et al. (2003) VEGF modulates early heart valve formation. Anat Rec A Discov Mol Cell Evol Biol 271: 202-208.
    [13] Stankunas K, Ma GK, Kuhnert FJ, et al. (2010) VEGF signaling has distinct spatiotemporal roles during heart valve development. Developmental Biology 347: 325-336. doi: 10.1016/j.ydbio.2010.08.030
    [14] Stevens A, Soden J, Brenchley PE, et al. (2003) Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter. Cancer Res 63: 812-816.
    [15] Watson CJ, Webb NJ, Bottomley MJ, et al. (2000) Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine 12: 1232-1235. doi: 10.1006/cyto.2000.0692
    [16] Vannay A, Vasarhelyi B, Kornyei M, et al. (2006) Single-nucleotide polymorphisms of VEGF gene are associated with risk of congenital valvuloseptal heart defects. American Heart Journal 151: 878-881. doi: 10.1016/j.ahj.2005.10.012
    [17] Smedts HP, Isaacs A, de Costa D, et al. VEGF polymorphisms are associated with endocardial cushion defects: a family-based case-control study. Pediatric Research 67: 23-28.
    [18] Miquerol L, Langille BL, Nagy A (2000) Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development 127: 3941-3946.
    [19] Gale NW, Dominguez MG, Noguera I, et al. (2004) Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci USA 101: 15949-15954. doi: 10.1073/pnas.0407290101
    [20] Pierpont MEM, Markwald RR, Lin AE (2000) Genetic aspects of atrioventricular septal defects. American Journal of Medical Genetics 97: 289-296. doi: 10.1002/1096-8628(200024)97:4<289::AID-AJMG1279>3.0.CO;2-U
    [21] Zhian S, Belmont J, Maslen CL (2012) Specific association of missense mutations in CRELD1 with cardiac atrioventricular septal defects in heterotaxy syndrome. Am J Med Genet A 158A: 2047-2049. doi: 10.1002/ajmg.a.35457
    [22] Enciso JM, Gratzinger D, Camenisch TD, et al. (2003) Elevated glucose inhibits VEGF-A-mediated endocardial cushion formation: modulation by PECAM-1 and MMP-2. Journal of Cell Biology 160: 605-615. doi: 10.1083/jcb.200209014
    [23] Rupp PA, Fouad GT, Egelston CA, et al. (2002) Identification, genomic organization and mRNA expression of CRELD1, the founding member of a unique family of matricellular proteins. Gene 293: 47-57. doi: 10.1016/S0378-1119(02)00696-0
    [24] Camenisch TD, Molin DG, Person A, et al. (2002) Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis. Developmental Biology 248: 170-181. doi: 10.1006/dbio.2002.0731
    [25] Camenisch TD, Schroeder JA, Bradley J, et al. (2002) Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2-ErbB3 receptors. Nature Medicine 8: 850-855.

    © 2014 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
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