Introduction: Insulinomatosis is a rare disorder characterised by persistent hyperinsulinaemic hypoglycaemia (PHH) due to the occurrence of multifocal pancreatic insulinomas. This condition, whose pathogenesis is unknown, can occur in a familial setting. Paradoxically, while some family members develop PHH, others develop diabetes mellitus.
Methods: We have identified a family with autosomal dominant familial insulinomatosis and diabetes. Exome sequencing was employed to identify the disease causing mutation. Functional in vitro studies were undertaken to characterise the effects of the identified mutation.
Results: A novel missense heterozygous mutation was identified in the transactivation domain of the islet-enriched transcription factor MAFA, and was found to segregate with both the insulinomatosis and diabetes phenotype. MAFA regulates the expression of several genes involved in glucose-stimulated insulin secretion, and its levels and activity are acutely induced in the presence of high glucose concentrations. Phosphorylation within the transactivation domain drives the proteosomal degradation of MAFA. MAFA has oncogenic transformation potential, and rearrangements leading to the overexpression of large MAF proteins play a pathogenic role in haematological malignancies.
In vitro, the mutation was found to impair phosphorylation within the transactivation domain of MAFA. No significant effect was observed in the transactivation activity, while the stability of mutant MAFA was profoundly increased in HEK293 cells. Notably, in the EndoC-βH1 human beta cell line, mutant MAFA was extremely stable, even at low glucose concentrations, when wild type MAFA is normally undetectable.
Conclusion: We report, for the first time, that a mutation in the transcription factor MAFA leads to familial insulinomatosis and diabetes. We hypothesise that dysregulation of MAFA turnover impairs glucose-stimulated insulin secretion, causing beta cell dysfunction and diabetes. At the same time, increased levels of MAFA are expected to induce cell transformation, leading to the development of insulinomatosis.
07 Nov 2016 - 09 Nov 2016