title: Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C.
abstract: Meconium ileus, intestinal obstruction in the newborn, is caused in most cases by CFTR mutations modulated by yet-unidentified modifier genes. We now show that in two unrelated consanguineous Bedouin kindreds, an autosomal-recessive phenotype of meconium ileus that is not associated with cystic fibrosis (CF) is caused by different homozygous mutations in GUCY2C, leading to a dramatic reduction or fully abrogating the enzymatic activity of the encoded guanlyl cyclase 2C. GUCY2C is a transmembrane receptor whose extracellular domain is activated by either the endogenous ligands, guanylin and related peptide uroguanylin, or by an external ligand, Escherichia coli (E. coli) heat-stable enterotoxin STa. GUCY2C is expressed in the human intestine, and the encoded protein activates the CFTR protein through local generation of cGMP. Thus, GUCY2C is a likely candidate modifier of the meconium ileus phenotype in CF. Because GUCY2C heterozygous and homozygous mutant mice are resistant to E. coli STa enterotoxin-induced diarrhea, it is plausible that GUCY2C mutations in the desert-dwelling Bedouin kindred are of selective advantage.
authors.affiliation: The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev, Ben Gurion University, Beer-Sheva 84105, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Romi
authors.forename: Idan
authors.initials: I
authors.lastname: Cohen
authors.forename: Daniella
authors.initials: D
authors.lastname: Landau
authors.forename: Suliman
authors.initials: S
authors.lastname: Alkrinawi
authors.forename: Baruch
authors.initials: B
authors.lastname: Yerushalmi
authors.forename: Reli
authors.initials: R
authors.lastname: Hershkovitz
authors.forename: Nitza
authors.initials: N
authors.lastname: Newman-Heiman
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
authors.forename: Rivka
authors.initials: R
authors.lastname: Ofir
authors.forename: Sara
authors.initials: S
authors.lastname: Sivan
authors.forename: Ohad S
authors.initials: OS
authors.lastname: Birk
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism / Q000633:toxicity; D006152:Cyclic GMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D003967:Diarrhea / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation; D004768:Enterotoxins / Q000378:metabolism / Q000633:toxicity; D029968:Escherichia coli Proteins; D005260:Female; D005768:Gastrointestinal Hormones / Q000378:metabolism; D060045:Genes, Modifier; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007415:Intestinal Obstruction / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008470:Meconium / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D045265:Natriuretic Peptides / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled / Q000235:genetics* / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D018000:Receptors, Peptide; C034151:heat stable toxin (E coli); D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C072685:guanylin; C084362:uroguanylin; C000613654:GUCY2C protein, human; C000613655:Gucy2c protein, mouse; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D006152:Cyclic GMP