期刊
GUT
卷 65, 期 8, 页码 1306-1313出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2015-309441
关键词
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资金
- Jubilaumsfonds der Osterreichischen National bank [14496]
- Tiroler Wissenschaftsfonds [UNI-0404/1286]
- Department of Biotechnology and Science and Technology, Government of India
- Indian Institute of Science
- Department of Science and Technology, Government of India
- Bill and Melinda Gates Foundation [OPP1106646] Funding Source: Bill and Melinda Gates Foundation
- Bill & Melinda Gates Foundation - Grand Challenges Explorations Initiative [OPP1106646] Funding Source: researchfish
Objective Congenital 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. Design We 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. Results We 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. Conclusions Dominant 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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