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Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease
Centre National de la Recherche Scientifique (CNRS), UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris, France.
Centre National de la Recherche Scientifique (CNRS), UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris, France.
Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).ORCID-id: 0000-0001-9401-6844
Centre National de la Recherche Scientifique (CNRS), UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris, France; Sorbonne Université, UMR7622-IBPS, Paris, France.
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2021 (engelsk)Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 254, nr 1, s. 31-45Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
John Wiley & Sons, 2021. Vol. 254, nr 1, s. 31-45
Emneord [en]
exocrine dysfunction, glucose intolerance, haploinsufficiency, HNF1B, maturity-onset diabetes of the young (MODY), optical projection tomography (OPT), pancreatic hypoplasia, pancreatitis, primary cilia, β-cells
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Identifikatorer
URN: urn:nbn:se:umu:diva-181833DOI: 10.1002/path.5629ISI: 000630230000001PubMedID: 33527355Scopus ID: 2-s2.0-85102621816OAI: oai:DiVA.org:umu-181833DiVA, id: diva2:1542060
Tilgjengelig fra: 2021-04-06 Laget: 2021-04-06 Sist oppdatert: 2022-04-19bibliografisk kontrollert

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