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Series GSE31260 Query DataSets for GSE31260
Status Public on Apr 10, 2012
Title Familial dominant diarrhea caused by an activating GUCY2C mutation is also associated with inflammatory bowel disease
Organism Homo sapiens
Experiment type Genome variation profiling by SNP array
SNP genotyping by SNP array
Summary 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.
 
Overall design 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.
 
Contributor(s) Fiskerstrand T
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Submission date Aug 08, 2011
Last update date May 17, 2017
Contact name Torunn Fiskerstrand
E-mail(s) torunn.fiskerstrand@netcom.no, torunn.fiskerstrand@helse-bergen.no
Phone +4755975481
Fax +4755975479
Organization name Haukeland University Hospital
Department Center for medical genetics and molecular medicine
Street address Jonas Lies vei
City Bergen
ZIP/Postal code 5021
Country Norway
 
Platforms (1)
GPL3718 [Mapping250K_Nsp] Affymetrix Mapping 250K Nsp SNP Array
Samples (25)
GSM774802 Family branch A_affected individual A-IV1
GSM774803 Family branch A_affected individual A-IV4
GSM774804 Family branch A_healthy individual A-IV7
Relations
BioProject PRJNA144831

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE31260_RAW.tar 725.4 Mb (http)(custom) TAR (of CEL, CHP)
Processed data provided as supplementary file
Processed data included within Sample table
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