Kantonsspital St.Gallen

missense mutation causes familial insulinomatosis and diabetes mellitus

Donato Iacovazzo, Sarah E Flanagan, Emily Walker, Rosana Quezado, Fernando Antonio De Sousa Barros, Richard Caswell, Matthew B Johnson, Matthew Wakeling, Michael Brändle, Min Guo, Mary N Dang, Plamena Gabrovska, Bruno Niederle, Emanuel Christ, Stefan Jenni, Bence Sipos, Maike Nieser, Andrea Frilling, Ketan Dhatariya, Philippe Chanson, Wouter W De Herder, Björn Konukiewitz, Günter Klöppel, Roland Stein, Márta Korbonits & Sian Ellard

abstract 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 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 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 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 mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity.
citation Iacovazzo D, Flanagan S E, Walker E, Quezado R, de Sousa Barros F A, Caswell R, Johnson M B, Wakeling M, Brändle M, Guo M, Dang M N, Gabrovska P, Niederle B, Christ E, Jenni S, Sipos B, Nieser M, Frilling A, Dhatariya K, Chanson P, de Herder W W, Konukiewitz B, Klöppel G, Stein R, Korbonits M, Ellard S. missense mutation causes familial insulinomatosis and diabetes mellitus. Proc Natl Acad Sci USA 2018; 115:1027-1032.
type journal paper/review (English)
date of publishing 16-01-2018
journal title Proc Natl Acad Sci USA (115/5)
ISSN electronic 1091-6490
pages 1027-1032
PubMed 29339498
DOI 10.1073/pnas.1712262115