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 journalArticle

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.

Original languageEnglish (US)
Pages (from-to)893-899
Number of pages7
JournalAmerican Journal of Human Genetics
Volume90
Issue number5
DOIs
StatePublished - May 4 2012

Fingerprint

Meconium
Ileus
Guanylate Cyclase
Cystic Fibrosis
Mutation
Modifier Genes
Escherichia coli
Ligands
Phenotype
Cystic Fibrosis Transmembrane Conductance Regulator
Intestinal Obstruction
Intestines
Diarrhea
Hot Temperature
Peptides
Proteins
heat stable toxin (E coli)

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Romi, H., Cohen, I., Landau, D., Alkrinawi, S., Yerushalmi, B., Hershkovitz, R., ... Birk, O. S. (2012). Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. American Journal of Human Genetics, 90(5), 893-899. https://doi.org/10.1016/j.ajhg.2012.03.022

Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. / Romi, Hila; Cohen, Idan; Landau, Daniella; Alkrinawi, Suliman; Yerushalmi, Baruch; Hershkovitz, Reli; Newman-Heiman, Nitza; Cutting, Garry R; Ofir, Rivka; Sivan, Sara; Birk, Ohad S.

In: American Journal of Human Genetics, Vol. 90, No. 5, 04.05.2012, p. 893-899.

Research output: Contribution to journalArticle

Romi, H, Cohen, I, Landau, D, Alkrinawi, S, Yerushalmi, B, Hershkovitz, R, Newman-Heiman, N, Cutting, GR, Ofir, R, Sivan, S & Birk, OS 2012, 'Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C', American Journal of Human Genetics, vol. 90, no. 5, pp. 893-899. https://doi.org/10.1016/j.ajhg.2012.03.022
Romi, Hila ; Cohen, Idan ; Landau, Daniella ; Alkrinawi, Suliman ; Yerushalmi, Baruch ; Hershkovitz, Reli ; Newman-Heiman, Nitza ; Cutting, Garry R ; Ofir, Rivka ; Sivan, Sara ; Birk, Ohad S. / Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 5. pp. 893-899.
@article{7080c6ec42e94bd082ef95398995fe2f,
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.",
author = "Hila Romi and Idan Cohen and Daniella Landau and Suliman Alkrinawi and Baruch Yerushalmi and Reli Hershkovitz and Nitza Newman-Heiman and Cutting, {Garry R} and Rivka Ofir and Sara Sivan and Birk, {Ohad S.}",
year = "2012",
month = "5",
day = "4",
doi = "10.1016/j.ajhg.2012.03.022",
language = "English (US)",
volume = "90",
pages = "893--899",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "5",

}

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.

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

UR - http://www.scopus.com/inward/citedby.url?scp=84860715301&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2012.03.022

DO - 10.1016/j.ajhg.2012.03.022

M3 - Article

C2 - 22521417

AN - SCOPUS:84860715301

VL - 90

SP - 893

EP - 899

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -