Dataset Information

Prolonged intestinal transit and diarrhea in patients with an activating GUCY2C mutation.

ABSTRACT:

Introduction

Increased intestinal hydration by activation of the epithelial enzyme linked receptor guanylate cyclase C (GC-C) is a pharmacological principle for treating constipation. Activating mutations in the GUCY2C gene encoding GC-C cause Familial GUCY2C diarrhea syndrome (FGDS) which has been diagnosed with severe dysmotility.

Aim

To investigate gut motility and hormones before and after a meal in FGDS patients and compare with healthy controls (HC).

Subjects and methods

Bristol stool chart and stool frequency was assessed. Before and after a meal occlusive and non-occlusive contractions were obtained using ultrasound. A wireless motility capsule (WMC) recorded gut transit time, pH, contractions and pressure. Plasma levels of selected gut hormones were measured at different time points.

Results

The FGDS patients had 4 (range 1-10) loose stools/day and prolonged total gut transit time compared to HC, 55.5 h vs 28.5 h, respectively,with significantly increased colon transit time. In FGDS patients, pH in duodenum, small bowel and colon was increased and the number of contractions and the intraluminal pressure were significantly decreased, measured by WMC. Ultrasound showed in small bowel increased number of non-occlusive contractions in the FGDS patients. Serotonin (5-HT) plasma levels in the HC peaked 30 min after the meal, while the FGDS patients had no response.

Conclusion

Despite having diarrhea, the FGDS patients have prolonged transit time through the gut compared to HC, particularly in colon. The reduced number of intestinal contractions and lack of 5-HT release after a meal in FGDS patients surprisingly resemble colonic motility disturbances seen in patients with constipation.

SUBMITTER: von Volkmann HL

PROVIDER: S-EPMC5619782 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Prolonged intestinal transit and diarrhea in patients with an activating GUCY2C mutation.

von Volkmann Hilde L HL Brønstad Ingeborg I Gilja Odd Helge OH R Tronstad Rune R Sangnes Dag Andre DA Nortvedt Ragnar R Hausken Trygve T Dimcevski Georg G Fiskerstrand Torunn T Nylund Kim K

PloS one 20170928 9

<h4>Introduction</h4>Increased intestinal hydration by activation of the epithelial enzyme linked receptor guanylate cyclase C (GC-C) is a pharmacological principle for treating constipation. Activating mutations in the GUCY2C gene encoding GC-C cause Familial GUCY2C diarrhea syndrome (FGDS) which has been diagnosed with severe dysmotility.<h4>Aim</h4>To investigate gut motility and hormones before and after a meal in FGDS patients and compare with healthy controls (HC).<h4>Subjects and methods< ...[more]

PMID: 28957388

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Project description:BACKGROUND Familial diarrheas are mostly severe recessive diseases. Here we describe the clinical picture and dominant genetic cause of a novel disease in 32 members of a Norwegian family. The chronic diarrhea is of early onset, relatively mild, and is combined with increased susceptibility to intestinal inflammation, ileus and oesophagitis. METHODS Whole genome SNP-analysis was used to identify a single candidate locus for dominant diarrhea on chromosome 12, followed by sequencing of the GU2CY gene. This encodes guanylyl cyclase 2C, an intestinal receptor for bacterial heat-stable enterotoxins and the peptides uroguanylin and guanylin. Functional studies of a missense mutation were performed after heterologous expression of the mutant receptor in HEK293T cells. The therapeutic response to metformin, an inhibitor of the cystic fibrosis transmembrane regulator (CFTR), was investigated in 5 patients. RESULTS We identified heterozygosity for the first described pathogenic human mutation (c.2519G>T ) in the GUCY2C gene. The mutant receptor showed increased cGMP production in response to its ligands. This may cause hyperactivation of the CFTR and consequent increased chloride and water secretion from the enterocytes, resulting in chronic diarrhea. Treatment with the CFTR-inhibitor metformin significantly reduced the frequency of stools in affected individuals by 34-45%. CONCLUSIONS Increased GC-C signaling disturbs normal bowel function, as shown by the diverse symptoms in our patients, and seems to have a pro-inflammatory effect, either through increased Cl- secretion or additional effects of elevated cellular cGMP. The importance of genetic variants in the GC-C-CFTR-pathway for conditions like Crohn’s disease and IBS should be further explored. Linkage analysis was performed (Allegro v 2.0) using Affymetrix 250K SNP arrays according to the manufacturer's directions on DNA extracted from peripheral blood samples. This accession number contains the data for 25 individuals of family branch A in the article.

Dataset Information

Prolonged intestinal transit and diarrhea in patients with an activating GUCY2C mutation.

Introduction

Aim

Subjects and methods

Results

Conclusion

Publications

Prolonged intestinal transit and diarrhea in patients with an activating GUCY2C mutation.

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