Familial diarrhea syndrome caused by an activating GUCY2C mutation

N Engl J Med. 2012 Apr 26;366(17):1586-95. doi: 10.1056/NEJMoa1110132. Epub 2012 Mar 21.


Background: Familial diarrhea disorders are, in most cases, severe and caused by recessive mutations. We describe the cause of a novel dominant disease in 32 members of a Norwegian family. The affected members have chronic diarrhea that is of early onset, is relatively mild, and is associated with increased susceptibility to inflammatory bowel disease, small-bowel obstruction, and esophagitis.

Methods: We used linkage analysis, based on arrays with single-nucleotide polymorphisms, to identify a candidate region on chromosome 12 and then sequenced GUCY2C, encoding guanylate cyclase C (GC-C), an intestinal receptor for bacterial heat-stable enterotoxins. We performed exome sequencing of the entire candidate region from three affected family members, to exclude the possibility that mutations in genes other than GUCY2C could cause or contribute to susceptibility to the disease. We carried out functional studies of mutant GC-C using HEK293T cells.

Results: We identified a heterozygous missense mutation (c.2519G→T) in GUCY2C in all affected family members and observed no other rare variants in the exons of genes in the candidate region. Exposure of the mutant receptor to its ligands resulted in markedly increased production of cyclic guanosine monophosphate (cGMP). This may cause hyperactivation of the cystic fibrosis transmembrane regulator (CFTR), leading to increased chloride and water secretion from the enterocytes, and may thus explain the chronic diarrhea in the affected family members.

Conclusions: Increased GC-C signaling disturbs normal bowel function and appears to have a proinflammatory effect, either through increased chloride secretion or additional effects of elevated cellular cGMP. Further investigation of the relevance of genetic variants affecting the GC-C-CFTR pathway to conditions such as Crohn's disease is warranted. (Funded by Helse Vest [Western Norway Regional Health Authority] and the Department of Science and Technology, Government of India.).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chronic Disease
  • Cyclic GMP / biosynthesis
  • Diarrhea / genetics*
  • Diarrhea / metabolism
  • Female
  • Genetic Linkage
  • Heterozygote
  • Humans
  • Male
  • Mutation, Missense*
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Receptors, Enterotoxin
  • Receptors, Guanylate Cyclase-Coupled / genetics*
  • Receptors, Guanylate Cyclase-Coupled / metabolism
  • Receptors, Peptide / genetics*
  • Receptors, Peptide / metabolism
  • Signal Transduction


  • Receptors, Peptide
  • GUCY2C protein, human
  • Receptors, Enterotoxin
  • Receptors, Guanylate Cyclase-Coupled
  • Cyclic GMP