MAFA missense mutation causes familial insulinomatosis and diabetes mellitus
Antonio de Sousa, F
de Herder, W
Proceedings of the National Academy of Sciences
National Academy of Sciences
Copyright © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND): https://creativecommons.org/licenses/by-nc-nd/4.0/
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 novel 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 as 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.
Grant support from Diabetes UK, the UK National Institute of Health Research (NIHR), and the US National Institutes of Health (DK-090750 to R.S., DK-109577 to E.W.) is gratefully acknowledged. D.I. is supported by a George Alberti Research Training Fellowship funded by Diabetes UK (16/0005395). S.E.F. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (105636/Z/14/Z). S.E. holds a Wellcome Trust Senior Investigator Award (098395/Z/12/A).
This is the author accepted manuscript. The final version is available from National Academy of Sciences via the DOI in this record.
Published online 16 January 2018