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Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects

Nature Genetics volume 26, pages 365–369 (2000)Cite this article

A Correction to this article was published on 01 December 2000

Abstract

All vertebrates display a characteristic asymmetry of internal organs with the cardiac apex, stomach and spleen towards the left, and the liver and gall bladder on the right1,2,3. Left-right (L-R) axis abnormalities or laterality defects are common in humans (1 in 8,500 live births). Several genes (such as Nodal, Ebaf and Pitx2) have been implicated in L-R organ positioning in model organisms2,3,4. In humans, relatively few genes have been associated with a small percentage of human situs defects. These include ZIC3 (ref. 5), LEFTB (formerly LEFTY2; ref. 6) and ACVR2B (encoding activin receptor IIB; ref. 7). The EGF-CFC genes8, mouse Cfc1 (encoding the Cryptic protein; ref. 9) and zebrafish one-eyed pinhead (oep; refs 10, 11) are essential for the establishment of the L-R axis12,13. EGF-CFC proteins act as co-factors for Nodal-related signals11, which have also been implicated in L-R axis development4. Here we identify loss-of-function mutations in human CFC1 (encoding the CRYPTIC protein) in patients with heterotaxic phenotypes (randomized organ positioning). The mutant proteins have aberrant cellular localization in transfected cells and are functionally defective in a zebrafish oep-mutant rescue assay. Our findings indicate that the essential role of EGF-CFC genes and Nodal signalling in left-right axis formation is conserved from fish to humans. Moreover, our results support a role for environmental and/or genetic modifiers in determining the ultimate phenotype in humans.

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Figure 1: Genomic structure and sequence alignment of CFC1.
Figure 2: Cellular localization of wild-type and variant CRYPTIC proteins in transfected COS cells.
Figure 3: Activities of CFC1 mutations in zebrafish embryos.

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Acknowledgements

We thank the patients and their families for participation. R.D.B. is supported by a postdoctoral fellowship from the Damon Runyon-Walter Winchell Cancer Research Fund. A.F.S. is a Scholar of the McKnight Endowment Fund for Neuroscience. The authors are supported by grants from the NIH (B.C., A.F.S. and M.M.S.), the US Army Breast Cancer Research Program (M.M.S.) and the Division of Intramural Research, National Human Genome Research Institute, NIH (M.M.).

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Author notes

  1. Erich Roessler, Rebecca D. Burdine and Umay Şaplakoğlu: These authors contributed equally to this work.

Authors and Affiliations

  1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA

    Richard N. Bamford, Erich Roessler, June dela Cruz & Maximilian Muenke

  2. Department of Cell Biology, Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA

    Rebecca D. Burdine & Alexander F. Schier

  3. Center for Advanced Biotechnology and Medicine and Department of Pediatrics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA

    Umay Şaplakoğlu & Michael M. Shen

  4. Department of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, UK

    Miranda Splitt

  5. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

    Jeffrey Towbin

  6. Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA

    Peter Bowers

  7. Department of Cardiology, Bambino Gesu' Children's Hospital, Rome, Italy

    Bruno Marino

  8. Department of Pathology, Baylor College of Medicine, Houston, Texas, USA

    Brett Casey

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Correspondence to Maximilian Muenke.

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Bamford, R., Roessler, E., Burdine, R. et al. Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet 26, 365–369 (2000). https://doi.org/10.1038/81695

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