Publication

missense mutation causes familial insulinomatosis and diabetes mellitus

Journal Paper/Review - Jan 16, 2018

Units
PubMed
Doi

Citation
Iacovazzo D, Jenni S, Sipos B, Nieser M, Frilling A, Dhatariya K, Chanson P, de Herder W, Konukiewitz B, Klöppel G, Stein R, Korbonits M, Christ E, Niederle B, Flanagan S, Walker E, Quezado R, de Sousa Barros F, Caswell R, Johnson M, Wakeling M, Brändle M, Guo M, Dang M, Gabrovska P, Ellard S. missense mutation causes familial insulinomatosis and diabetes mellitus. Proc Natl Acad Sci USA 2018; 115:1027-1032.
Type
Journal Paper/Review (English)
Journal
Proc Natl Acad Sci USA 2018; 115
Publication Date
Jan 16, 2018
Issn Electronic
1091-6490
Pages
1027-1032
Brief description/objective

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.