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Nature Genetics  26, 365 - 369 (2000)

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

Richard N. Bamford1, Erich Roessler1, 9, Rebecca D. Burdine2, 9, Umay S cedilaplakolu3, 9, June dela Cruz1, Miranda Splitt4, Jeffrey Towbin5, Peter Bowers6, Bruno Marino7, Alexander F. Schier2, Michael M. Shen3, Maximilian Muenke1 & Brett Casey8

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

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

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

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

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

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

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

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

9  These authors contributed equally to this work.

Correspondence should be addressed to Maximilian Muenke
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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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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