MAFA missense mutation causes familial insulinomatosis and diabetes mellitus

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 5; pp. 1027 - 1032
• Main Authors: Iacovazzo, Donato, Flanagan, Sarah E., Walker, Emily, Quezado, Rosana, de Sousa Barros, Fernando Antonio, Caswell, Richard, Johnson, Matthew B., Wakeling, Matthew, Brändle, Michael, Guo, Min, Dang, Mary N., Gabrovska, Plamena, Niederle, Bruno, Christ, Emanuel, Jenni, Stefan, Sipos, Bence, Nieser, Maike, Frilling, Andrea, Dhatariya, Ketan, Chanson, Philippe, de Herder, Wouter W., Konukiewitz, Björn, Klöppel, Günter, Stein, Roland, Korbonits, Márta, Ellard, Sian
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 30.01.2018
• Subjects: Autosomal dominant inheritance; Biological Sciences; Biotechnology; Diabetes; Diabetes mellitus; Diabetes Mellitus - genetics; Diabetes Mellitus - metabolism; Diabetes Mellitus - pathology; Female; Females; Genes, Dominant; Genetic transformation; Genotype & phenotype; Glaucoma; Glucose; Heredity; Homozygotes; Human performance; Humans; Hyperinsulinism - genetics; Hyperinsulinism - metabolism; Hyperinsulinism - pathology; Hypoglycemia; Insulin; Insulin secretion; Insulinoma - genetics; Insulinoma - metabolism; Insulinoma - pathology; Maf Transcription Factors, Large - genetics; Maf Transcription Factors, Large - metabolism; MafA protein; Male; Males; Missense mutation; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Mutation, Missense; Neuroendocrine tumors; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - metabolism; Neuroendocrine Tumors - pathology; Pancreas; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Patients; Pedigree; Phenotypes; Phosphorylation; Protein Stability; Secretion; Stability; Transcriptional Activation; Tumors; Whole Exome Sequencing; insulinomatosis; MODY; MAFA; diabetes; insulinoma
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1712262115

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.