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Familial Diarrhea Syndrome Caused by an Activating GUCY2C Mutation

Fiskerstrand, Torunn and Arshad, Najla and Haukanes, Bjorn Ivar and Tronstad, Rune Rose and Pham, Khanh Do-Cong and Johansson, Stefan and Havik, Bjarte and Tonder, Siv L and Levy, Shawn E and Brackman, Damien and Boman, Helge and Biswas, Kabir Hassan and Apold, Jaran and Hovdenak, Nils and Visweswariah, Sandhya S and Knappskog, Per M (2012) Familial Diarrhea Syndrome Caused by an Activating GUCY2C Mutation. In: New England Journal of Medicine, 366 (17). pp. 1586-1595.

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Official URL: http://www.nejm.org/doi/full/10.1056/NEJMoa1110132


BACKGROUND Familial diarrhea disorders are, in most cases, severe and caused by recessive mutations. We describe the cause of a novel dominant disease in 32 members of a Norwegian family. The affected members have chronic diarrhea that is of early onset, is relatively mild, and is associated with increased susceptibility to inflammatory bowel disease, small-bowel obstruction, and esophagitis. METHODS We used linkage analysis, based on arrays with single-nucleotide polymorphisms, to identify a candidate region on chromosome 12 and then sequenced GUCY2C, encoding guanylate cyclase C (GC-C), an intestinal receptor for bacterial heat-stable enterotoxins. We performed exome sequencing of the entire candidate region from three affected family members, to exclude the possibility that mutations in genes other than GUCY2C could cause or contribute to susceptibility to the disease. We carried out functional studies of mutant GC-C using HEK293T cells. RESULTS We identified a heterozygous missense mutation (c.2519G -> T) in GUCY2C in all affected family members and observed no other rare variants in the exons of genes in the candidate region. Exposure of the mutant receptor to its ligands resulted in markedly increased production of cyclic guanosine monophosphate (cGMP). This may cause hyperactivation of the cystic fibrosis transmembrane regulator (CFTR), leading to increased chloride and water secretion from the enterocytes, and may thus explain the chronic diarrhea in the affected family members. CONCLUSIONS Increased GC-C signaling disturbs normal bowel function and appears to have a proinflammatory effect, either through increased chloride secretion or additional effects of elevated cellular cGMP. Further investigation of the relevance of genetic variants affecting the GC-C-CFTR pathway to conditions such as Crohn's disease is warranted. (Funded by Helse Vest Western Norway Regional Health Authority] and the Department of Science and Technology, Government of India.)

Item Type: Journal Article
Publication: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Additional Information: Copyright of this article is belongs to Massachusetts Medical Society.
Department/Centre: Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited: 22 Aug 2012 04:39
Last Modified: 22 Aug 2012 06:52
URI: http://eprints.iisc.ac.in/id/eprint/44448

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