Alt. symbols: GUC2C | STAR

Approved name: guanylate cyclase 2C
Alt. names: guanylate cyclase 2C (heat stable enterotoxin receptor) | STA receptor, heat stable enterotoxin receptor

Location: 12p12.3: 14612632 - 14696599 (-)
Gene type: protein_coding, 2 transcripts.

Scores: LoFtool: 0.374000 | pLI: 0.00000000 | LOEUF: 1.079

HGNC: 4688

NCBI: 2984, RefSeq: NG_052021.1

Ensembl: ENSG00000070019.5

LRG_ | Status: none

OMIM: 601330

Expression | ProteinAtlas

GUCY2C encodes guanylyl cyclase 2C, which catalyzes synthesis of cyclic GMP (cGMP) from GTP (PMID: 1718270, 11950846, 23269669, 22521417, 22436048). Largely restricted to the intestinal tract, this transmembrane protein is expressed as a homodimer on the apical brush border of intestinal epithelial cells from the duodenum to the rectum, with its ligand-binding extracellular domain facing the intestinal lumen and its intracellular catalytic domain facing the cytosol (PMID: 30131940). It can be activated by E.coli heat-stable enterotoxin (HST), the causative agent of traveler's diarrhea, and by the endogenous peptides guanylin and uroguanylin (PMID: 14675035). Ligand binding activates the catalytic domain, generating intracellular cGMP, leading to phosphorylation and translocation of the cystic fibrosis transmembrane conductance regulator (CFTR) to the cell surface, triggering Cl− and HCO3- efflux into the intestinal lumen (PMID: 26677983, 27481254, 28592587). Additionally, cGMP signaling inhibits an apical Na+/H+ exchanger to prevent Na+ absorption from the lumen. Thus, the combined electrolyte efflux and retention in the lumen produces an osmotic gradient that drives fluid secretion and results in secretory diarrhea.

Biallelic loss-of-function variants (Asp387Gly, Asn757LysfsTer2, Ala670Thr, Cys928Arg) in GUCY2C have been associated with autosomal recessive meconium ileus [OMIM: 614665] (PMID: 22521417, 25370039). In contrast, heterozygous gain-of-function mutations are associated with an autosomal dominant form of congenital diarrhea [OMIM: 614616], featuring relatively mild, early-onset chronic diarrhea that may be associated with increased susceptibility to inflammatory bowel disease (IBD), small bowel ob struction (SBO), and esophagitis. Multiple patients with GUCY2C mutations have been noted to present with Crohn’s disease (CD)–like symptoms and colitis in addition to diarrhea (PMID: 22436048, 25994218). In addition to significant alterations of their gut microbiome (PMID: 28902124), patients have multiple, fluid-filled small bowel loops with incomplete contractions and impaired colonic mobility (PMID: 26835907, 27338166, 28957388), all of which may contribute to their increased risks for IBS, IBD and SBO. Of note, patients have also been found to harbor retinal drusen-like deposits (PMID: 29979251). Fiskerstrand et al. (2012) identified the heterozygous variant Ser840Ile in a large family and showed that it segregated only with affected members (PMID: 22436048). Transfection studies showed increased cGMP production compared to wildtype, suggesting a gain-of-function effect. Subsequently, Mueller et al. (2016) characterized an additional four activating mutations in unrelated European children also presenting with severe and debilitating diarrhea, sometimes even noticed in utero (PMID: 25994218). The mutations (Lys507Glu, Leu775Pro, Arg792Ser, Asn850Asp) affected different domains of the receptor, including the kinase-homology, linker and catalytic domains (PMID: 32293781, 30420416). More recently, Wolfe et al. (2021) identified heterozygous variant Asp794Val in a Mennonite patient with chronic diarrhea and an extensive maternal family history of chronic diarrhea and bowel dilatation (PMID: 33949097). Segregation analysis showed that all family members who were heterozygous for this variant had GI‐related symptoms and the variant showed increased cGMP production in cell lines when stimulated with E. coli heat‐stable enterotoxin STp (HST). Potential candidate therapies in the form of guanylyl cyclase inhibitors have been studied for treating the diarrhea (PMID: 33949097, 34797252). [Load More]