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

Evans Quilichini (1, 2) , Mélanie Fabre (1, 2) , Christoffer Nord (3) , Thassadite Dirami (1, 2) , Axelle Le Marec (1, 2) , Silvia Cereghini (1, 2) , Raymond C Pasek (4) , Maureen Gannon (4) , Ulf Ahlgren (3) , Cécile Haumaitre (1, 2)

1 LBD - Laboratoire de Biologie du Développement [IBPS]
2 IBPS - Institut de Biologie Paris Seine
3 Umeå University
4 Vanderbilt University Medical Center [Nashville]

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 (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.

Mots clés: pancreatitis; HNF1B; maturity-onset diabetes of the young (MODY); haploinsufficiency; glucose intolerance; primary cilia; exocrine dysfunction; pancreatic hypoplasia; β-cells; optical projection tomography (OPT)

Domaines: Sciences du Vivant [q-bio]

Evans Quilichini, Mélanie Fabre, Christoffer Nord, Thassadite Dirami, Axelle Le Marec, et al.. Insights into the etiology and physiopathology of MODY5 / HNF1B pancreatic phenotype with a mouse model of the human disease. Journal of Pathology, 2021, 254, pp.31-45. ⟨10.1002/path.5629⟩. ⟨hal-03977649⟩