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Transient PAX8 Expression in Islets During Pregnancy Correlates With β-Cell Survival, Revealing a Novel Candidate Gene in Gestational Diabetes Mellitus

Martin-Montalvo, Alejandro
López-Noriega, Livia
Jiménez-Moreno, Carmen
Herranz, Amanda
Lorenzo, Petra I
Cobo-Vuilleumier, Nadia
Tamayo, Alejandra
González-Guerrero, Cristian
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Published in Diabetes. 2019, vol. 68, no. 1, p. 109-118
Abstract Transient Pax8 expression was reported in mouse islets during gestation, whereas a genome-wide linkage and admixture mapping study highlighted PAX8 as a candidate gene for diabetes mellitus (DM). We sought the significance of PAX8 expression in mouse and human islet biology. PAX8 was induced in gestating mouse islets and in human islets treated with recombinant prolactin. Global gene expression profiling of human and mouse islets overexpressing the corresponding species-specific PAX8 revealed the modulation of distinct genetic pathways that converge on cell survival. Accordingly, apoptosis was reduced in PAX8-overexpressing islets. These findings support that PAX8 could be a candidate gene for the study of gestational DM (GDM). PAX8 was genotyped in patients with GDM and gestational thyroid dysfunction (GTD), a pathology commonly found in patients with mutations on PAX8 A novel missense PAX8 mutation (p.T356M, c.1067C>T) was identified in a female diagnosed with GDM and GTD as well as in her father with type 2 DM but was absent in control patients. The p.T356M variant did not alter protein stability or cellular localization, whereas its transactivation activity was hindered. In parallel, a retrospective clinical analysis uncovered that a pregnant female harboring a second PAX8 mutation (p.P25R, c.74C>G) previously reported to cause congenital hypothyroidism also developed GDM. These data indicate that increased expression of PAX8 affects islet viability and that PAX8 could be considered as a candidate gene for the study of GDM.
Keywords AnimalsCell Survival/genetics/physiologyDiabetes, Gestational/genetics/metabolismFemaleGenotypeGlucose Tolerance TestHumansImmunohistochemistryMice, Inbred C57BLMutation/geneticsMutation, Missense/geneticsPAX8 Transcription Factor/genetics/metabolismPedigreePregnancyRetrospective Studies
PMID: 30352879
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Research groups Création de tissus par bio-ingénieurie et régénération d'organes (1021)
La transplantation d'îlots de Langerhans (623)
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MARTIN-MONTALVO, Alejandro et al. Transient PAX8 Expression in Islets During Pregnancy Correlates With β-Cell Survival, Revealing a Novel Candidate Gene in Gestational Diabetes Mellitus. In: Diabetes, 2019, vol. 68, n° 1, p. 109-118. doi: 10.2337/db18-0285 https://archive-ouverte.unige.ch/unige:138454

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Deposited on : 2020-07-16

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