Neurogenin-3 (NEUROG3) is expressed in endocrine progenitor cells, and is required for endocrine-cell development in the pancreas and intestine.
The NEUROG3 gene is therefore a candidate for the cause of a newly discovered autosomal recessive disorder.
It is characterized by generalized malabsorption and a paucity of enteroendocrine cells.
Dr Martín and colleagues from California screened genomic DNA from 3 unrelated patients with sparse enteroendocrine cells for mutations of NEUROG3.
The investigative team then tested the ability of the observed mutations to alter NEUROG3 function, using in vitro and in vivo assays.
|Mutations rendered the NEUROG3 protein unable to activate it's downstream target|
|New England Journal of Medicine|
The investigators found that patients had few intestinal enteroendocrine cells positive for chromogranin A.
However, the patients had normal numbers of Paneth's, goblet, and absorptive cells.
The team identified 2 homozygous mutations in NEUROG3.
Both of these mutations rendered the NEUROG3 protein unable to activate NEUROD1, a downstream target of NEUROG3.
The investigators noted that the mutations compromised the ability of NEUROG3 to bind to an E-box element in the NEUROD1 promoter.
Dr Martín's team concludes, “A newly discovered disorder characterized by malabsorptive diarrhea and a lack of intestinal enteroendocrine cells is caused by loss-of-function mutations in NEUROG3.”