Meconium ileus in a Lebanese family secondary to mutations in the GUCY2C gene

Smith, Amanda; Bulman, Dennis E.; Goldsmith, Claire; Bareke, Eric; Majewski, Jacek; Boycott, Kym M.; Nikkel, Sarah M.

doi:10.1038/ejhg.2014.236

Cited by 25 publications

(20 citation statements)

References 8 publications

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“…Children in a Lebanese family presenting with MI harbored a change at Ala670 to Thr due to a transition of G>A at base 2008 (Figure 3b; Table 1). 33 We predict that this mutation would be pathogenic and result in inactivation of GC‐C, in agreement with the MI seen in this patient. Ala670 is conserved across species except in fishes, where it is replaced with Ser.…”

Section: Kinase‐homology Domainsupporting

confidence: 87%

Mutational landscape of receptor guanylyl cyclase C: Functional analysis and disease‐related mutations

2020

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Guanylyl cyclase C (GC-C) is the receptor for the heat-stable enterotoxin, which causes diarrhea, and the endogenous ligands, guanylin and uroguanylin. GC-C is predominantly expressed in the intestinal epithelium and regulates fluid and ion secretion in the gut. The receptor has a complex domain organization, and in the absence of structural information, mutational analysis provides clues to mechanisms of regulation of this protein. Here, we review the mutational landscape of this receptor that reveals regulatory features critical for its activity. We also summarize the available information on mutations in GC-C that have been reported in humans and contribute to severe gastrointestinal abnormalities. Since GC-C is also expressed in extraintestinal tissues, it is likely that mutations thus far reported in humans may also affect other organ systems, warranting a close observation of these patients in future. K E Y W O R D ScGMP, guanylyl cyclase C, human mutation, meconium ileus, secretory diarrhea

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Section: Kinase‐homology Domainsupporting

confidence: 87%

Mutational landscape of receptor guanylyl cyclase C: Functional analysis and disease‐related mutations

2020

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“…This flow of anions drives electrogenic sodium efflux, producing an osmotic gradient that ultimately results in fluid accumulation in the intestinal lumen manifesting as diarrhea (Dekkers et al, 2013). Consistent with these findings, families with activating or inactivating mutations in GUCY2C exhibit changes in fluid secretion that are consistent with this secretory function (Fiskerstrand et al, 2012;Romi et al, 2012;Muller et al, 2015;Smith et al, 2015).…”

Section: Gucy2c Signaling and The Paracrine Hormone Hypothesis Of Colsupporting

confidence: 69%

Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer

et al. 2016

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Obesity has emerged as a principal cause of mortality worldwide, reflecting comorbidities including cancer risk, particularly in colorectum. Although this relationship is established epidemiologically, molecular mechanisms linking colorectal cancer and obesity continue to be refined. Guanylyl cyclase C (GUCY2C), a membrane-bound guanylyl cyclase expressed in intestinal epithelial cells, binds the paracrine hormones guanylin and uroguanylin, inducing cGMP signaling in colorectum and small intestine, respectively. Guanylin is the most commonly lost gene product in sporadic colorectal cancer, and its universal loss early in transformation silences GUCY2C, a tumor suppressor, disrupting epithelial homeostasis underlying tumorigenesis. In small intestine, eating induces endocrine secretion of uroguanylin, the afferent limb of a novel gut-brain axis that activates hypothalamic GUCY2C-cGMP signaling mediating satiety opposing obesity. Recent studies revealed that dietinduced obesity suppressed guanylin and uroguanylin expression in mice and humans. Hormone loss reflects reversible calorieinduced endoplasmic reticulum stress and the associated unfolded protein response, rather than the endocrine, adipokine, or inflammatory milieu of obesity. Loss of intestinal uroguanylin secretion silences the hypothalamic GUCY2C endocrine axis, creating a feed-forward loop contributing to hyperphagia in obesity. Importantly, calorie-induced guanylin loss silences the GUCY2C-cGMP paracrine axis underlying obesity-induced epithelial dysfunction and colorectal tumorigenesis. Indeed, genetically enforced guanylin replacement eliminated diet-induced intestinal tumorigenesis in mice. Taken together, these observations suggest that GUCY2C hormone axes are at the intersection of obesity and colorectal cancer. Moreover, they suggest that hormone replacement that restores GUCY2C signaling may be a novel therapeutic paradigm to prevent both hyperphagia and intestinal tumorigenesis in obesity.

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“…This mutation resulted in increased sensitivity of GC-C to its endogenous ligands guanylin and uroguanylin and to the heat-stable enterotoxin (ST) of Escherichia coli , giving rise to increased levels of cyclic guanosine monophosphate ( cGMP) in the epithelial cell, resulting in enhanced fluid and ion secretion, and diarrhoea. In contrast, inactivating mutations of GUCY2C in three Bedouin families resulted in meconium ileus 6 7 as a consequence of diminished fluid and ion secretion that is normally maintained by the action of guanylin and uroguanylin on GC-C.…”

Section: Introductionmentioning

confidence: 89%

Congenital secretory diarrhoea caused by activating germline mutations inGUCY2C

Müller

Rasool

Heinz‐Erian

et al. 2015

Gut

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ObjectiveCongenital sodium diarrhoea (CSD) refers to a form of secretory diarrhoea with intrauterine onset and high faecal losses of sodium without congenital malformations. The molecular basis for CSD remains unknown. We clinically characterised a cohort of infants with CSD and set out to identify disease-causing mutations by genome-wide genetic testing.DesignWe performed whole-exome sequencing and chromosomal microarray analyses in 4 unrelated patients, followed by confirmatory Sanger sequencing of the likely disease-causing mutations in patients and in their family members, followed by functional studies.ResultsWe identified novel de novo missense mutations in GUCY2C, the gene encoding receptor guanylate cyclase C (GC-C) in 4 patients with CSD. One patient developed severe, early-onset IBD and chronic arthritis at 4 years of age. GC-C is an intestinal brush border membrane-bound guanylate cyclase, which functions as receptor for guanylin, uroguanylin and Escherichia coli heat-stable enterotoxin. Mutations in GUCY2C were present in different intracellular domains of GC-C, and were activating mutations that enhanced intracellular cyclic guanosine monophosphate accumulation in a ligand-independent and ligand-stimulated manner, following heterologous expression in HEK293T cells.ConclusionsDominant gain-of-function GUCY2C mutations lead to elevated intracellular cyclic guanosine monophosphate levels and could explain the chronic diarrhoea as a result of decreased intestinal sodium and water absorption and increased chloride secretion. Thus, mutations in GUCY2C indicate a role for this receptor in the pathogenesis of sporadic CSD.

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Meconium ileus in a Lebanese family secondary to mutations in the GUCY2C gene

Cited by 25 publications

References 8 publications

Mutational landscape of receptor guanylyl cyclase C: Functional analysis and disease‐related mutations

Mutational landscape of receptor guanylyl cyclase C: Functional analysis and disease‐related mutations

Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer

Congenital secretory diarrhoea caused by activating germline mutations inGUCY2C

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