TY - JOUR
T1 - Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C
AU - Romi, Hila
AU - Cohen, Idan
AU - Landau, Daniella
AU - Alkrinawi, Suliman
AU - Yerushalmi, Baruch
AU - Hershkovitz, Reli
AU - Newman-Heiman, Nitza
AU - Cutting, Garry R.
AU - Ofir, Rivka
AU - Sivan, Sara
AU - Birk, Ohad S.
N1 - Funding Information:
This work was funded through a grant from the U.S. Cystic Fibrosis Foundation. We thank the Morris Kahn Family Foundation for the kind support. Facilities used were donated in part by the Wolfson Foundation and the Wolfson Family Charitable Trust. G.R.C. was supported through National Institutes of Health grants NHLBI HL068927 and NIDDK DK 044003.
PY - 2012/5/4
Y1 - 2012/5/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84860715301&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.03.022
DO - 10.1016/j.ajhg.2012.03.022
M3 - Article
AN - SCOPUS:84860715301
SN - 0002-9297
VL - 90
SP - 893
EP - 899
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -