PUBLICATION
Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects
- Authors
- 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.
- ID
- ZDB-PUB-001107-3
- Date
- 2000
- Source
- Nature Genetics 26(3): 365-369 (Journal)
- Registered Authors
- Burdine, Rebecca, Schier, Alexander
- Keywords
- none
- MeSH Terms
-
- Point Mutation
- Situs Inversus/genetics
- Holoprosencephaly/genetics*
- Abnormalities, Multiple/embryology
- Abnormalities, Multiple/genetics*
- Molecular Sequence Data
- Recombinant Fusion Proteins/metabolism
- Embryo, Nonmammalian/abnormalities
- Amino Acid Sequence
- Dextrocardia/embryology
- Dextrocardia/genetics
- Frameshift Mutation
- Head/abnormalities*
- Head/embryology
- DNA Mutational Analysis
- Codon/genetics
- Open Reading Frames
- Viscera/abnormalities*
- Polymorphism, Single-Stranded Conformational
- Intercellular Signaling Peptides and Proteins*
- Transfection
- Mice
- Zebrafish/embryology
- Zebrafish/genetics
- Sequence Alignment
- Amino Acid Substitution
- Embryonic and Fetal Development/genetics*
- Expressed Sequence Tags
- Morphogenesis/genetics*
- Fetal Proteins/genetics
- DNA, Complementary/genetics
- Species Specificity
- Sequence Deletion
- Phenotype
- Animals
- Genotype
- Sequence Homology, Amino Acid
- Growth Substances/deficiency
- Growth Substances/genetics*
- Humans
- PubMed
- 11062482 Full text @ Nat. Genet.
Citation
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. (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.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping