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Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):1027-1032. doi: 10.1073/pnas.1712262115. Epub 2018 Jan 16.

MAFA missense mutation causes familial insulinomatosis and diabetes mellitus.

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Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, United Kingdom.
Institute of Biomedical and Clinical Science, University of Exeter Medical School, EX2 5DW Exeter, United Kingdom.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232.
Serviço de Endocrinologia e Diabetes, Hospital Universitário Walter Cantídio, Universidade Federal do Ceará, 60430-372 Fortaleza, Brazil.
Division of Endocrinology and Diabetes, Department of Internal Medicine, Kantonsspital St. Gallen, CH-9007 St. Gallen, Switzerland.
Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, University of Vienna, A-1090 Vienna, Austria.
Division of Diabetes, Endocrinology and Metabolism, University Hospital of Basel, CH-4031 Basel, Switzerland.
Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Bern, Inselspital, CH-3010 Bern, Switzerland.
Department of Pathology, University of Tübingen, 72076 Tübingen, Germany.
Department of Surgery and Cancer, Imperial College London, W12 0HS London, United Kingdom.
Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, NR4 7UY Norwich, United Kingdom.
Service d'Endocrinologie et des Maladies de la Reproduction, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, F-94275 Le Kremlin-Bicêtre, France.
INSERM 1185, Faculté de Médicine Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France.
Department of Internal Medicine, Sector of Endocrinology, ENETS Centre of Excellence for Neuroendocrine Tumors, Erasmus MC, 3015 Rotterdam, The Netherlands.
Department of Pathology, Consultation Center for Pancreatic and Endocrine Tumors, Technical University of Munich, 81675 Munich, Germany.
Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, United Kingdom;


The β-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic MAFA mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four females). Four patients from the index family, including two homozygotes, had a history of congenital cataract and/or glaucoma. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in β-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in β-cell lines was enhanced compared with wild-type MAFA. In summary, the p.Ser64Phe missense MAFA mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity.


MAFA; MODY; diabetes; insulinoma; insulinomatosis

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Conflict of interest statement

The authors declare no conflict of interest.

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