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

Abstract

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 Hnf1bsp2/+ 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 Hnf1bsp2/+ displays glucose intolerance. Whereas Hnf1bsp2/+ 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 Hnf1bsp2/+ 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 Hnf1bsp2/+ 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.

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

“…In most MODY subtypes, the exact pathological mechanisms of disease progression are still unknown. This is due to the inaccessibility of human pancreatic tissue and the fact that rodent models do not recapitulate the MODY disease phenotype [ 146 , 147 , 148 ], with the exception of HNF1B-MODY [ 149 ]. Therefore, currently human-induced pluripotent stem cells (hiPSCs)-based disease modelling tools are being developed aiming to resolve some of the pathological mechanisms of MODY, and possibly reveal new therapeutic strategies for the patients.…”

Potter Deformation Sequence Caused by 17q12 Deletion: A Lethal Constellation

“…16,17 Also, disruption of HNF1B in murine pancreatic progenitors causes hypoplasia, with loss of acinar cells, decreased endocrine precursors, and ductal cyst formation. 18,19 Phenotypic severity of mouse models of HNF1B mutation is affected by murine genetic background, so unknown modifiers may contribute to clinical disease heterogeneity. 16 Also, while 17q12 deletions are associated with neuropsychiatric diagnoses, intragenic mutations of HNF1B do not have this effect, thus other mechanisms of disease remain to be identified.…”

10 Years of GWAS discovery in endometrial cancer: Aetiology, function and translation

“… 42 , 43 Notably, KLF5 and HNF1B have functions that are related to genetically established endometrial cancer risk factors: KLF5 is involved in adipocyte differentiation 44 ; and HNF1B is involved in insulin secretion. 45 …”