title: Mutant neurogenin-3 in congenital malabsorptive diarrhea.
abstract: 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.
authors.affiliation: Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital, Los Angeles, Calif, USA.
authors.forename: Jiafang
authors.initials: J
authors.lastname: Wang
authors.forename: Galen
authors.initials: G
authors.lastname: Cortina
authors.forename: S Vincent
authors.initials: SV
authors.lastname: Wu
authors.forename: Robert
authors.initials: R
authors.lastname: Tran
authors.forename: Jang-Hyeon
authors.initials: JH
authors.lastname: Cho
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Bailey
authors.forename: Milan
authors.initials: M
authors.lastname: Jamrich
authors.forename: Marvin E
authors.initials: ME
authors.lastname: Ament
authors.forename: William R
authors.initials: WR
authors.lastname: Treem
authors.forename: Ivor D
authors.initials: ID
authors.lastname: Hill
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Vargas
authors.forename: George
authors.initials: G
authors.lastname: Gershman
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Farmer
authors.forename: Laurie
authors.initials: L
authors.lastname: Reyen
authors.forename: Martín G
authors.initials: MG
authors.lastname: Martín
mesh_terms: 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
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C093970:NEUROD1 protein, human; C498695:NEUROG3 protein, human