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

Hila Romi, Idan Cohen, Daniella Landau, Suliman Alkrinawi, Baruch Yerushalmi, Reli Hershkovitz, Nitza Newman-Heiman, Garry R. Cutting, Rivka Ofir, Sara Sivan, Ohad S. Birk

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


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.

Original languageEnglish
Pages (from-to)893-899
Number of pages7
JournalAmerican Journal of Human Genetics
Issue number5
StatePublished - 4 May 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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