Biallelic mutations of the gene encoding the transcription factor NEUROG3 are associated with a rare disorder that presents in neonates as generalized malabsorption — due to a complete absence of enteroendocrine cells — followed, in early childhood or beyond, by insulin-dependent diabetes mellitus (IDDM). The commonly delayed onset of IDDM suggests a differential requirement for NEUROG3 in endocrine cell generation in the human pancreas versus the intestine. However, previously identified human mutations were hypomorphic and, hence, may have had residual function in pancreas. We report 2 patients with biallelic functionally null variants of the NEUROG3 gene who nonetheless did not present with IDDM during infancy but instead developed permanent IDDM during middle childhood ages. The variants showed no evidence of function in traditional promoter-based assays of NEUROG3 function and also failed to exhibit function in a variety of potentially novel in vitro and in vivo molecular assays designed to discern residual NEUROG3 function. These findings imply that, unlike in mice, pancreatic endocrine cell generation in humans is not entirely dependent on NEUROG3 expression and, hence, suggest the presence of unidentified redundant in vivo pathways in human pancreas capable of yielding β cell mass sufficient to maintain euglycemia until early childhood.
R. Sergio Solorzano-Vargas, Matthew Bjerknes, Jiafang Wang, S. Vincent Wu, Manuel G. Garcia-Careaga, Pisit Pitukcheewanont, Hazel Cheng, Michael S. German, Senta Georgia, Martín G. Martín
Submitter: Marianne Voz | mvoz@uliege.be
Authors: Marianne Voz and Lydie Flasse
GIGA, Uliege
Published March 27, 2020
Dear Editor of JCI insight,
We did read with great interest the study of Solorzano-Vargas that reports two patients with biallelic functionally null variants of the NEUROG3 gene but who nonetheless did not present diabetes mellitus during infancy. They hypothesize the presence of unidentified redundant in vivo pathways in human pancreas capable of yielding β cell mass sufficient to maintain euglycemia until early childhood.
This study reinforces our statement that we published in BMC biology (Flasse et al., 2013) demonstrating that NEUROG3 is not the unique pancreatic endocrine cell fate determinant in vertebrates. Indeed, we show that in zebrafish Neurog3 does not control pancreatic endocrine cell differentiation but its function is fulfilled by two other ARP/ASCL factors, Ascl1b and Neurod1. In fact, a general survey of endocrine cell fate determinants in the whole digestive system among vertebrates indicates that these determinants all belong to the ARP/ASCL family but not necessarily to the Neurog3 subfamily. The identity of the ARP/ASCL factor involved depends not only on the organ but also on the species.
We believe that our work provides a clue about the identity of the unidentified redundant in vivo pathway Solorzano-Vargas et al. mentioned. The role of NEUROG3 as a unique key determinant of β-cell generation in human has been subject to debate for years and we are glad to see that the work you just published is unravelling the query and support our own conclusion.
Yours sincerely
Marianne Voz and Lydie Flasse
Flasse, L.C., Pirson, J.L., Stern, D.G., Von Berg, V., Manfroid, I., Peers, B., and Voz, M.L. (2013). Ascl1b and Neurod1, instead of Neurog3, control pancreatic endocrine cell fate in zebrafish. BMC Biol. 11, 78.