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    • br GC C and cGMP of mice and

    2022-05-10


    GC-C and cGMP: of mice and men As is usually the case for many genes, most of the studies that relate to GC-C have to date been carried out in mouse models, or in cell lines derived from human colorectal cancer tissue. What appeared to be a lacuna was any report of a human disorder that resulted from a mutation in the GC-C gene, GUCY2C. However, this year, two studies appeared where point mutations in GUCY2C were associated with human disease. The importance of these two findings in emphasizing the role of GC-C in human intestinal physiology cannot be overstated. Familial diarrheas are severe and generally caused by recessive mutations. Irritable bowel syndrome and Crohn’s disease are well documented examples that show a genetic predisposition, and are generally believed to be multifactorial, with a number of genetic susceptible loci contributing to their occurrence in families. Recently, a large Norwegian family was identified which demonstrated a dominantly inherited, fully penetrant syndrome of frequent diarrhea. Whole genome SNP-linkage based analysis and exome sequencing identified a heterozygous mutation in GUCY2C[14]. The effect of the Ser840 mutation to an Ile in GC-C was characterized by heterologous Retapamulin sale of the mutant receptor. The mutation interestingly resulted in a hyper-responsive form of GC-C, whereby levels of cGMP produced by the mutant receptor were 6–10-fold higher than observed for the wild type receptor, at equivalent concentrations of ST peptide, uroguanylin or guanylin. What was intriguing was that while the affinity of mutant GC-C for ST or uroguanylin did not change, the EC50 for activation by uroguanylin was significantly lower in the mutant receptor in comparison with the wild type receptor [14]. We therefore argued that patients harboring this mutation would have elicited higher intracellular levels of cGMP in the intestine in response to the endogenous levels of uroguanylin or guanylin present in their gastrointestinal tract. Thus, this mutant GC-C was a gain-of-function mutation, which would have resulted in over-activation of signaling pathways that emanate from GC-C. One such pathway may regulate fluid and ion secretion from the intestine, and involve activation of CFTR and inhibition of NHE3, thus resulting in the chronic and frequent episodes of diarrhea that these patients experience. What remained enigmatic, however, were the additional severe symptoms reported by some patients [14]. Some individuals had undergone laparotomy for suspected bowel obstruction, and ileal inflammation, volvulus or adhesional bands, was confirmed. Some showed anatomical variants in the ileocaecal region, and needed to undergo resection of the terminal ileum or caecum. In addition, Crohn’s disease was observed in four of such patients. No emotional disturbances, which could be a consequence of hyperactive GC-C in neurons [35], were observed in any patients, and no one showed any signs of leanness [33]. Clearly, the presence of over active GC-C, and presumably elevated levels of cGMP, in these patients led to phenotypes that could not be predicted from results seen in the GC-C knock-out mice. The increased risk of inflammatory bowel disease in these patients could have been a consequence of enhanced inflammatory cytokine production, as has been observed in NHE3 null mice [50], [56], and patients suffering from chloride diarrhea [49]. It could be speculated that, in contrast to the GC-C knock-out mouse, hyperactive GC-C could have led to a breakdown of intestinal barrier function, resulting in the inflammation that is seen in these patients. Alternatively, as discussed above, the microbiota of these patients may differ, consequent to the life-long incidence of diarrhea, resulting in an increased susceptibility to inflammation. Following this first report of a human disease correlated with a gain-of-function mutation in the GUCY2C gene, inactivating mutations of GC-C in a small Bedouin population were reported [15]. These patients also reported multiple disturbances, which led to ileus, and blockage of the small intestine caused by thick mucoid stools, presumably as a result of the lack of adequate fluid being secreted via the GC-C signaling pathway. Here again, these results contrast with mice data, where the GC-C knock-out mouse was normal in terms of regular gastrointestinal function. Two inactivating mutations were reported in the Bedouin population, one which was a substitution of Asp387 by a Gly residue, which reduced cGMP production by ∼ 50% in the mutant receptor in contrast with the wild type receptor. The second was an insertion of a single base following Asn757, which would have truncated the receptor protein before the guanylyl cyclase domain, causing the mutant protein to be non-responsive to ligands of GC-C. The authors speculate that these mutations would have rendered the carriers resistant to ST-induced diarrhea, which could have been an advantage to the desert dwelling Bedouins [15].