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Maturity‐onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of  HNF1B . No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human  HNF1B  splicing mutation at the intron‐2 splice donor site in the mouse genome. This  Hnf1b   sp2/+   model generated with targeted mutation of  Hnf1b  mimicking the c.544+1G>T (<IVS2nt+1G>T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native  Hnf1b  transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model  Hnf1b   sp2/+   displays glucose intolerance. Whereas  Hnf1b   sp2/+   isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total  β ‐cell volume. These defects were associated with a 30% decrease in expression of the pro‐endocrine gene  Neurog3  that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the  Hnf1b   sp2/+   pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar‐to‐ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the  Hnf1b   sp2/+   mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique  in vivo  tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research. © 2021 The Authors.  The Journal of Pathology  published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Insights into the etiology and physiopathology of MODY5 / HNF1B pancreatic phenotype with a mouse model of the human disease