Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C

Am J Hum Genet. 2012 May 4;90(5):893-9. doi: 10.1016/j.ajhg.2012.03.022. Epub 2012 Apr 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bacterial Toxins / metabolism
  • Bacterial Toxins / toxicity
  • Cyclic GMP / metabolism
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / physiopathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Diarrhea / etiology
  • Diarrhea / metabolism
  • Diarrhea / physiopathology
  • Down-Regulation
  • Enterotoxins / metabolism
  • Enterotoxins / toxicity
  • Escherichia coli Proteins
  • Female
  • Gastrointestinal Hormones / metabolism
  • Genes, Modifier
  • HEK293 Cells
  • Heterozygote
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestinal Obstruction / genetics*
  • Intestinal Obstruction / metabolism*
  • Intestinal Obstruction / physiopathology
  • Male
  • Meconium / metabolism*
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Natriuretic Peptides / metabolism
  • Pedigree
  • Phenotype
  • Receptors, Enterotoxin
  • Receptors, Guanylate Cyclase-Coupled / genetics*
  • Receptors, Guanylate Cyclase-Coupled / metabolism
  • Receptors, Peptide / genetics*
  • Receptors, Peptide / metabolism


  • Bacterial Toxins
  • Enterotoxins
  • Escherichia coli Proteins
  • Gastrointestinal Hormones
  • Natriuretic Peptides
  • Receptors, Peptide
  • heat stable toxin (E coli)
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • guanylin
  • uroguanylin
  • GUCY2C protein, human
  • Gucy2c protein, mouse
  • Receptors, Enterotoxin
  • Receptors, Guanylate Cyclase-Coupled
  • Cyclic GMP