[HTML][HTML] Mutant neurogenin-3 in congenital malabsorptive diarrhea
J Wang, G Cortina, SV Wu, R Tran… - … England Journal of …, 2006 - Mass Medical Soc
J Wang, G Cortina, SV Wu, R Tran, JH Cho, MJ Tsai, TJ Bailey, M Jamrich, ME Ament…
New England Journal of Medicine, 2006•Mass Medical SocBackground 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 …
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 …
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.
The New England Journal Of Medicine