ZFIN ID: ZDB-PUB-001107-3
Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects
Bamford, R.N., Roessler, E., Burdine, R.D., Saplakoglu, U., de la Cruz, J., Splitt, M., Towbin, J., Bowers, P., Marino, B., Schier, A.F., Shen, M.M., Muenke, M., and Casey, B.
Date: 2000
Source: Nature Genetics   26(3): 365-369 (Journal)
Registered Authors: Burdine, Rebecca, Schier, Alexander
Keywords: none
MeSH Terms:
  • Abnormalities, Multiple/embryology
  • Abnormalities, Multiple/genetics*
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Codon/genetics
  • DNA Mutational Analysis
  • DNA, Complementary/genetics
  • Dextrocardia/embryology
  • Dextrocardia/genetics
  • Embryo, Nonmammalian/abnormalities
  • Embryonic and Fetal Development/genetics*
  • Expressed Sequence Tags
  • Fetal Proteins/genetics
  • Frameshift Mutation
  • Genotype
  • Growth Substances/deficiency
  • Growth Substances/genetics*
  • Head/abnormalities*
  • Head/embryology
  • Holoprosencephaly/genetics*
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Mice
  • Molecular Sequence Data
  • Morphogenesis/genetics*
  • Open Reading Frames
  • Phenotype
  • Point Mutation
  • Polymorphism, Single-Stranded Conformational
  • Recombinant Fusion Proteins/metabolism
  • Sequence Alignment
  • Sequence Deletion
  • Sequence Homology, Amino Acid
  • Situs Inversus/genetics
  • Species Specificity
  • Transfection
  • Viscera/abnormalities*
  • Zebrafish/embryology
  • Zebrafish/genetics
PubMed: 11062482 Full text @ Nat. Genet.
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 right. 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 organisms. 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 genes, 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 axis. EGF-CFC proteins act as co-factors for Nodal-related signals, which have also been implicated in L-R axis development. 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.