title: Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects.
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.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: R N
authors.initials: RN
authors.lastname: Bamford
authors.forename: E
authors.initials: E
authors.lastname: Roessler
authors.forename: R D
authors.initials: RD
authors.lastname: Burdine
authors.forename: U
authors.initials: U
authors.lastname: Saplakoğlu
authors.forename: J
authors.initials: J
authors.lastname: dela Cruz
authors.forename: M
authors.initials: M
authors.lastname: Splitt
authors.forename: J A
authors.initials: JA
authors.lastname: Goodship
authors.forename: J
authors.initials: J
authors.lastname: Towbin
authors.forename: P
authors.initials: P
authors.lastname: Bowers
authors.forename: G B
authors.initials: GB
authors.lastname: Ferrero
authors.forename: B
authors.initials: B
authors.lastname: Marino
authors.forename: A F
authors.initials: AF
authors.lastname: Schier
authors.forename: M M
authors.initials: MM
authors.lastname: Shen
authors.forename: M
authors.initials: M
authors.lastname: Muenke
authors.forename: B
authors.initials: B
authors.lastname: Casey
mesh_terms: D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D003914:Dextrocardia / Q000196:embryology / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000002:abnormalities; D005314:Embryonic and Fetal Development / Q000235:genetics*; D020224:Expressed Sequence Tags; D005326:Fetal Proteins / Q000235:genetics; D016368:Frameshift Mutation; D005838:Genotype; D006133:Growth Substances / Q000172:deficiency / Q000235:genetics*; D006257:Head / Q000002:abnormalities* / Q000196:embryology; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics*; D016366:Open Reading Frames; D010641:Phenotype; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D012857:Situs Inversus / Q000235:genetics; D013045:Species Specificity; D014162:Transfection; D014781:Viscera / Q000002:abnormalities*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: C491268:CFC1 protein, human; C104433:Cfc1 protein, mouse; D003062:Codon; D018076:DNA, Complementary; D005326:Fetal Proteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins