Mutant neurogenin-3 in congenital malabsorptive diarrhea.
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.
Wang
Jiafang
J
Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital, Los Angeles, Calif, USA.
Cortina
Galen
G
Wu
S Vincent
SV
Tran
Robert
R
Cho
Jang-Hyeon
JH
Tsai
Ming-Jer
MJ
Bailey
Travis J
TJ
Jamrich
Milan
M
Ament
Marvin E
ME
Treem
William R
WR
Hill
Ivor D
ID
Vargas
Jorge H
JH
Gershman
George
G
Farmer
Douglas G
DG
Reyen
Laurie
L
Martín
Martín G
MG
D000595:Amino Acid Sequence; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002908:Chronic Disease; D003967:Diarrhea / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D019858:Enteroendocrine Cells / Q000473:pathology; D017809:Fatal Outcome; D006801:Humans; D007231:Infant, Newborn; D007421:Intestine, Small / Q000473:pathology*; D008286:Malabsorption Syndromes / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C093970:NEUROD1 protein, human; C498695:NEUROG3 protein, human