| Familial diarrhea syndrome caused by an activating GUCY2C mutation. | |
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MedLine Citation:
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PMID: 22436048 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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.). |
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Authors:
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Torunn Fiskerstrand; Najla Arshad; Bjørn Ivar Haukanes; Rune Rose Tronstad; Khanh Do-Cong Pham; Stefan Johansson; Bjarte Håvik; Siv L Tønder; Shawn E Levy; Damien Brackman; Helge Boman; Kabir Hassan Biswas; Jaran Apold; Nils Hovdenak; Sandhya S Visweswariah; Per M Knappskog |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-03-21 |
Journal Detail:
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Title: The New England journal of medicine Volume: 366 ISSN: 1533-4406 ISO Abbreviation: N. Engl. J. Med. Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-04-26 Completed Date: 2012-04-27 Revised Date: 2012-10-10 |
Medline Journal Info:
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Nlm Unique ID: 0255562 Medline TA: N Engl J Med Country: United States |
Other Details:
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Languages: eng Pagination: 1586-95 Citation Subset: AIM; IM |
Affiliation:
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Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway. torunn.fiskerstrand@helse-bergen.no |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Chronic Disease Cyclic GMP / biosynthesis Diarrhea / genetics*, metabolism Female Genetic Linkage Heterozygote Humans Male Mutation, Missense* Pedigree Polymorphism, Single Nucleotide Receptors, Guanylate Cyclase-Coupled / genetics*, metabolism Receptors, Peptide / genetics*, metabolism Signal Transduction |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Peptide; 7665-99-8/Cyclic GMP; EC 4.6.1.2/Receptors, Guanylate Cyclase-Coupled; EC 4.6.1.2/enterotoxin receptor |
| Comments/Corrections | |
Comment In:
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Clin Genet. 2012 Sep;82(3):221-2
[PMID:
22697041
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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