Alternative titles; symbols
HGNC Approved Gene Symbol: GUCY2C
SNOMEDCT: 206523001, 86092005; ICD10CM: P76.0;
Cytogenetic location: 12p12.3 Genomic coordinates (GRCh38): 12:14,612,632-14,696,599 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p12.3 | Diarrhea 6 | 614616 | Autosomal dominant | 3 |
| Meconium ileus | 614665 | Autosomal recessive | 3 |
Mann et al. (1996) described guanylyl cyclase C (called GC-C by them) as a transmembrane receptor expressed primarily in the intestine that regulates chloride secretion via the cystic fibrosis transmembrane conductance regulator (602421). Binding of GC-C to either the endogenous peptide guanylin (139392) or the bacterially derived heat-stable enterotoxin STa, results in increased levels of cGMP and the stimulation of water and chloride secretion. In the case of exposure to STa, this leads to debilitating secretory diarrhea.
From a human colonic cell line, Singh et al. (1991) isolated a cDNA whose predicted amino acid sequence is 81% homologous to the GC-C intestinal enterotoxin STa receptor in rat. After transient transfection of COS-7 cells with the human cDNA, the investigators observed a concentration-dependent response to STa in transfected cells as measured by intracellular cGMP accumulation. They referred to this human STa receptor as STaR. Similarly, de Sauvage et al. (1991) identified a human cDNA encoding an STa receptor. The receptor has an extracellular ligand-binding domain and a cytoplasmic guanylyl cyclase domain, as do members of the natriuretic peptide receptor family. They showed that stable mammalian cell lines overexpressing the STa receptor bind radioiodinated STa (with a K(d) in the nanomolar range) and exhibit a ligand-induced increase in the cellular cGMP level.
Mann et al. (1996) cloned and sequenced a cDNA for mouse Gucy2c.
Mann et al. (1996) mapped mouse Gucy2c by interspecific backcross to chromosome 6. The placement of the mouse gene between Tpi (190450) and Kras2 (190070), which map to human chromosome 12p13 and 12p12.1, respectively, suggested to the authors that the human GUC2C gene resides on 12p as well. This was confirmed by fluorescence in situ hybridization, which mapped the human GUC2C gene to 12p12.
Gong et al. (2011) reported that midbrain dopamine neurons in mice selectively express guanylyl cyclase C (GC-C), a membrane receptor theretofore thought to be expressed mainly in the intestine. GC-C activation potentiates the excitatory responses mediated by glutamate and acetylcholine receptors via the activity of guanosine 3-prime,5-prime-monophosphate-dependent protein kinase (PKG; 176894). Mice in which GC-C had been knocked out exhibited hyperactivity and attention deficits. Moreover, their behavioral phenotypes were reversed by ADHD therapeutics and a PKG activator. Gong et al. (2011) concluded that their results indicated important behavioral and physiologic functions for the GC-C/PKG signaling pathway within the brain and suggested new therapeutic targets for neuropsychiatric disorders related to the malfunctions of midbrain dopamine neurons.
Diarrhea 6
In affected members of a large pedigree segregating autosomal dominant early-onset chronic diarrhea mapping to chromosome 12p (DIAR6; 614616), Fiskerstrand et al. (2012) identified heterozygosity for a missense mutation in the GUCY2C gene (601330.0001) that was not found in unaffected family members or controls. Functional analysis suggested that the mutation has a gain-of-function effect, increasing ligand-mediated activation of guanylate cyclase-C with subsequent intracellular accumulation of cGMP. Based on associated features observed in some affected family members, Fiskerstrand et al. (2012) suggested that GUCY2C might be a susceptibility gene for Crohn disease (see 266600), small bowel obstruction, and functional gastrointestinal diseases such as irritable bowel syndrome.
Meconium Ileus
In 11 affected individuals from a large Bedouin kindred with meconium ileus mapping to chromosome 12p13 (614665), Romi et al. (2012) identified homozygosity for a missense mutation in the candidate gene GUCY2C (601330.0002). In a sporadic patient with meconium ileus from an unrelated Bedouin family, they identified homozygosity for a 1-bp duplication in the GUCY2C gene (601330.0003).
Valentino et al. (2011) showed that silencing of the intestinal epithelial transmembrane receptor GUCY2C led to obesity and metabolic syndrome in a knockout mouse model. Homozygous knockout mice were as much as 26% heavier than controls and had a higher adiposity index, hepatic steatosis, and elevated serum leptin. The knockout mice also had cardiac hypertrophy, hyperinsulinemia, and decreased glycemic control. The authors proposed that nutrient intake induces secretion of the inactive prouroguanylin protein along the crypt-villus axis. The prohormone is then converted to active uroguanylin in the hypothalamus, activating downstream pathways that lead to satiation.
In affected members from 3 branches of a large pedigree segregating autosomal dominant early-onset chronic diarrhea (DIAR6; 614616), Fiskerstrand et al. (2012) identified heterozygosity for a 2519G-T transversion in exon 22 of the GUCY2C gene, predicted to result in a ser840-to-ile (S840I) substitution at a highly conserved residue in the catalytic domain. Transfection studies demonstrated markedly increased production of cGMP with the mutant receptor compared to wildtype, suggesting a gain-of-function effect.
In affected members of a large Bedouin kindred with meconium ileus (614665), originally reported by Tal et al. (1985), Romi et al. (2012) identified homozygosity for a 1160A-G transition in the GUCY2C gene, resulting in an asp387-to-gly (D387G) substitution at a conserved residue within 1 of the 2 essential regions of the extracellular ligand-binding domain. The mutation was also found in homozygosity in 4 of 24 unaffected family members (1 of whom had meconium ileus detected prenatally but passed stools unassisted after birth), and was found in heterozygosity in 3 of 240 unrelated Bedouin controls, but was not reported in the HapMap or 1000 Genomes Project databases. Transfection studies in HEK293 cells demonstrated that activation of guanylate cyclase was 60% lower with the D387G mutant than with wildtype.
In a sporadic patient with severe meconium ileus (614665), born of first-cousin Bedouin parents, Romi et al. (2012) identified homozygosity for a 1-bp insertion (2270dupA) in the GUCY2C gene, causing a frameshift resulting in a premature termination codon (Asn757LysfsTer2) that fully abrogates the guanylate cyclase catalytic domain. The mutation was not found in 2 healthy sibs or in 240 unrelated Bedouin controls, and was not reported in the HapMap or 1000 Genomes Project databases. The patient, who had a normal sweat test, required surgery for her meconium ileus.
de Sauvage, F. J., Camerato, T. R., Goeddel, D. V. Primary structure and functional expression of the human receptor for Escherichia coli heat-stable enterotoxin. J. Biol. Chem. 266: 17912-17918, 1991. [PubMed: 1680854]
Fiskerstrand, T., Arshad, N., Haukanes, B. I., Tronstad, R. R., Pham, K. D.-C., Johansson, S., Havik, B., Tonder, S. L., Levy, S. E., Brackman, D., Boman, H., Biswas, K. H., Apold, J., Hovdenak, N., Visweswariah, S. S., Knappskog, P. M. Familial diarrhea syndrome caused by an activating GUCY2C mutation. New Eng. J. Med. 366: 1586-1595, 2012. [PubMed: 22436048] [Full Text: https://doi.org/10.1056/NEJMoa1110132]
Gong, R., Ding, C., Hu, J., Lu, Y., Liu, F., Mann, E., Xu, F., Cohen, M. B., Luo, M. Role for the membrane receptor guanylyl cyclase-C in attention deficiency and hyperactive behavior. Science 333: 1642-1646, 2011. [PubMed: 21835979] [Full Text: https://doi.org/10.1126/science.1207675]
Mann, E. A., Swenson, E. S., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Taguchi, T., Testa, J. R., Giannella, R. A. Localization of the guanylyl cyclase C gene to mouse chromosome 6 and human chromosome 12p12. Genomics 34: 265-267, 1996. [PubMed: 8661067] [Full Text: https://doi.org/10.1006/geno.1996.0284]
Romi, H., Cohen, I., Landau, D., Alkrinawi, S., Yerushalmi, B., Hershkovitz, R., Newman-Heiman, N., Cutting, G. R., Ofir, R., Sivan, S., Birk, O. S. Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. Am. J. Hum. Genet. 90: 893-899, 2012. [PubMed: 22521417] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.022]
Singh, S., Singh, G., Heim, J. M., Gerzer, R. Isolation and expression if a guanylate cyclase-coupled heat stable enterotoxin receptor cDNA from a human colonic cell line. Biochem. Biophys. Res. Commun. 179: 1455-1463, 1991. [PubMed: 1718270] [Full Text: https://doi.org/10.1016/0006-291x(91)91736-v]
Tal, A., Carmi, R., Chai-Am, E., Zirkin, H., Bar-Ziv, J., Freud, E. Familial meconium ileus with normal sweat electrolytes. Clin. Pediat. 24: 460-462, 1985. [PubMed: 4006357] [Full Text: https://doi.org/10.1177/000992288502400809]
Valentino, M. A., Lin, J. E., Snook, A. E., Li, P., Kim, G. W., Marszalowicz, G., Magee, M. S., Hyslop, T., Schulz, S., Waldman, S. A. A uroguanylin-GUCY2C endocrine axis regulates feeding in mice. J. Clin. Invest. 121: 3578-3588, 2011. [PubMed: 21865642] [Full Text: https://doi.org/10.1172/JCI57925]