Abstract
Cryptic (CFC1), a member of the epidermal growth factor–Cripto/FRL-1/Cryptic (EGF–CFC) gene family, is involved in the evolutionarily conserved establishment of left–right lateral asymmetry. Inactivation of Cfc1 in mice results in laterality defects and complex cardiac malformations. Similarly, mutations in the human CFC1 gene have been identified in patients with heterotaxy syndrome. The cardiac defects in humans resemble those in mice lacking Cfc1. We postulated that some patients with isolated cardiac malformations could also have mutations in the CFC1 gene. Our analysis of the CFC1 gene in 167 patients with congenital heart disease revealed a novel A145T missense variant in 3 patients with type II atrial septal defect. Furthermore, we found the previously characterized R78W polymorphism in another patient with type II atrial septal defect. However, the A145T sequence alteration was also identified in 3 controls, suggesting that this variant is a polymorphism. We conclude that CFC1 variants could be a rare cause of congenital heart disease in patients without laterality defects.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bamford RN, Roessler E, Burdine RD, et al. (2000) Loss-of-function mutations in the EGF-CFC gene CFCl are associated with human left–right laterality defects. Nat Genet 26:365–369
Basson CT, Huang T, Lin RC, et al. (1999) Different TBX5 interactions in heart and limb defined by Holt–Oram syndrome mutations. Proc Natl Acad Sci USA 96:2919–2924
Gaio U, Schweickert A, Fischer A, et al. (1999) A role of the cryptic gene in the correct establishment of the left–right axis. Curr Biol 9:1339–1342
Garg V, Kathiriya IS, Barnes R, et al. (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443–447
Geier C, Perrot A, Ozcelik C, et al. (2003) Mutations in the human muscle LIM protein gene in families with hypertrophic cardioniyopathy. Circulation 107:1390–1395
Goldmuntz E, Bamford R, Karkera JD, et al. (2002) CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. Am J Hum Genet 70:776–780
Kaemmerer H, Hess J (2005) Adult patients with congenital heart abnormalities: present and future. Dtsch Med Wochenschr 130:97–101
Schier AF, Neuhauss SC, Helde KA, Talbot WS, Driever W (1997) The one-eyed pinhead gene functions in mesoderm and endoderm formation in zebrafish and interacts with no tail. Development 124:327–342
Schott JJ, Benson DW, Basson CT, et al. (1998) Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281:108–110
Yan YT, Gritsman K, Ding J, et al. (1999) Conserved requirement for EGF–CFC genes in vertebrate left–right axis formation. Genes Dev 13:2527–2537
Yelon D (2001) Cardiac patterning and morphogenesis in zebrafish. Dev Dyn 222:552–563
Acknowledgments
We thank all the patients and probands for their participation and Meike Fitschen, Wolfgang Derer, and for support in the initial phase of this work. We are grateful to Friedrich C. Luft and Alistair N. Garratt for critically reading the manuscript. This work was funded by the Berlin Institute for Heart Research.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Özcelik, C., Bit-Avragim, N., Panek, A. et al. Mutations in the EGF-CFC Gene Cryptic Are an Infrequent Cause of Congenital Heart Disease. Pediatr Cardiol 27, 695–698 (2006). https://doi.org/10.1007/s00246-006-1082-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00246-006-1082-0