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Background Neurogenin-3 (NEUROG3) is expressed in endocrine progenitor cells and is required for endocrine-cell development in the pancreas and intestine. The NEUROG3 gene (NEUROG3) is therefore a candidate for the cause of a newly discovered autosomal recessive disorder characterized by generalized malabsorption and a paucity of enteroendocrine cells.
Methods We screened genomic DNA from three unrelated patients with sparse enteroendocrine cells for mutations of NEUROG3. We then tested the ability of the observed mutations to alter NEUROG3 function, using in vitro and in vivo assays.
Results The patients had few intestinal enteroendocrine cells positive for chromogranin A, but they had normal numbers of Paneth's, goblet, and absorptive cells. We identified two homozygous mutations in NEUROG3, both of which rendered the NEUROG3 protein unable to activate NEUROD1, a downstream target of NEUROG3, and compromised the ability of NEUROG3 to bind to an E-box element in the NEUROD1 promoter. The injection of wild-type but not mutant NEUROG3 messenger RNA into xenopus embryos induced NEUROD1 expression.
Conclusions A newly discovered disorder characterized by malabsorptive diarrhea and a lack of intestinal enteroendocrine cells is caused by loss-of-function mutations in NEUROG3.
Source Information
From the Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital (J.W., R.T., M.E.A., J.H.V., M.G.M.); the Department of Pathology and Laboratory Medicine (G.C.), Center for Ulcer Research and Education, Division of Digestive Diseases, the Department of Medicine (S.V.W.), and the Departments of Surgery (D.G.F.) and Nursing (L.R.), David Geffen School of Medicine, UCLA — all in Los Angeles; the Department of Molecular and Cellular Biology (J.-H.C., M.-J.T., M.J.) and Program in Developmental Biology (M.-J.T., T.J.B., M.J.), Baylor College of Medicine, Houston; the Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, State University of New York Downstate College of Medicine, Brooklyn (W.R.T.); the Department of Pediatrics, Division of Gastroenterology, Wake Forest University School of Medicine, Winston-Salem, N.C. (I.D.H.); and the Department of Pediatrics, Division of Gastroenterology at Harbor–UCLA Medical Center, David Geffen School of Medicine, UCLA, Torrance, Calif. (G.G.).
Address reprint requests to Dr. Martín at the David Geffen School of Medicine, UCLA, Department of Pediatrics, Gastroenterology, and Nutrition, 10833 Le Conte Ave., 12-383 MDCC, Los Angeles, CA 90095, or at mmartin{at}mednet.ucla.edu.
Related Letters:
Mutant Neurogenin-3 in Congenital Malabsorptive Diarrhea
Jensen J. N., Rosenberg L. C., Hecksher-Sørensen J., Serup P., Martín M. G., Wu S. V., Cortina G.
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N Engl J Med 2007;
356:1781-1782, Apr 26, 2007.
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