Congenital diarrhea is an uncommon yet devastating clinical condition that frequently leads to intestinal failure. Many patients with chronic/congenital diarrhea of early infancy have defects in a variety of transporters and enzymes that have important roles in the process of nutrient and ion digestion and absorption. Presently, a large proportion of children with congenital diarrhea have a generalized malabsorptive form that has not been well characterized clinically, and its molecular basis has yet to be elucidated. Recent studies in null mice have determined that two basic-helix-loop-helix (bHLH) transcriptional factors, mouse atonal homolog 1 (MATH1) and neurogenin-3 (ngn-3) influence enteroendocrine, Paneth, goblet and epithelial cell fate determination. In the preliminary results section of this grant, we present for the first time the clinical characteristics and molecular basis of a novel human disorder that presented with severe congenital malabsorptive diarrhea. Histological evaluation of two cases revealed an absence of small and large bowel enteroendocrine cells, while the other intestinal cell types, including Paneth, goblet and absorptive cells were of normal appearance. Molecular analysis identified two homozygous mutations in neurogenin-3 that alter highly conserved amino acid residues in the DNA binding domain of the neurogenin gene family. In this grant, our central hypothesis is that abnormalities of enteroendocrine cell development, resulting from loss-of-function mutations of ngn-3 (or its upstream regulator HATH1) are a common yet currently unappreciated cause of chronic malabsorptive diarrhea during early infancy. Therefore, to test our central hypothesis, we propose to: [1] assess whether loss-of-function mutations of neurogenin-3 is frequently seen in children that present with chronic congenital malabsorptive diarrhea; [2] whether mutations of HATH1, the regulator of neurogenin-3, can be identified in a subset of cases that present with congenital diarrhea during early infancy. The long-term objective of this proposal is to assess whether abnormalities of small bowel cell fate determination in humans are associated with gastrointestinal symptoms and other potential clinical problems. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK075009-01
Application #
7080886
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
May, Michael K
Project Start
2006-05-15
Project End
2008-04-30
Budget Start
2006-05-15
Budget End
2007-04-30
Support Year
1
Fiscal Year
2006
Total Cost
$154,500
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095