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

Richard N. Bamford, Erich Roessler, Rebecca D. Burdine, Umay Şaplakoǧlu, June Dela Cruz, Miranda Splitt, Jeffrey Towbin, Peter Bowers, Bruno Marino, Alexander F. Schier, Michael M. Shen, Maximilian Muenke, Brett Casey

Research output: Contribution to journalArticle

262 Scopus citations

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 right1-3 . 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 organisms2-4. 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.

Original languageEnglish (US)
Pages (from-to)365-369
Number of pages5
JournalNature Genetics
Volume26
Issue number3
DOIs
StatePublished - Nov 20 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics

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    Bamford, R. N., Roessler, E., Burdine, R. D., Şaplakoǧlu, U., Dela Cruz, J., Splitt, M., Towbin, J., Bowers, P., Marino, B., Schier, A. F., Shen, M. M., Muenke, M., & Casey, B. (2000). Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nature Genetics, 26(3), 365-369. https://doi.org/10.1038/81695