Association for
Multiple Endocrine
Neoplasia Disorders

A missense mutation in the islet-enriched transcription factor MAFA leads to familial insulinomatosis and diabetes

Donato Iacovazzo¹, Sarah E. Flanagan², Emily Walker³, Richard Caswell², Michael Brändle⁴, Matthew Johnson², Matthew Wakeling², Min Guo³, Mary N. Dang¹, Plamena Gabrovska¹, Bruno Niederle⁵, Emanuel Christ⁶, Stefan Jenni⁶, Bence Sipos⁷, Maike Nieser⁷, Andrea Frilling⁸, Ketan Dhatariya⁹, Philippe Chanson¹⁰, Wouter de Herder¹¹ & Björn Konukiewitz¹²

¹Centre for Endocrinology, Barts and The London School of Medicine, London, UK; ²Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK; ³Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, USA; ⁴Division of Endocrinology and Diabetes, Department of Internal Medicine, Kantonsspital St. Gallen, St. Gallen, Switzerland; ⁵Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, University of Vienna, Vienna, Austria; ⁶Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Bern, Inselspital, Bern, Switzerland; ⁷Department of Pathology, University of Tübingen, Tübingen, Germany; ⁸Department of Surgery and Cancer, Imperial College London, London, UK; ⁹Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK; ¹⁰Service d’Endocrinologie et des Maladies de la Reproduction, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France; ¹¹Department of Internal Medicine, Sector of Endocrinology, ENETS Centre of Excellence for Neuroendocrine Tumors, Erasmus MC, Rotterdam, The Netherlands; ¹²Department of Pathology, Consultation Center for Pancreatic and Endocrine Tumors, Technical University, Munich, Germany.

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.