Second MAFA Variant Causing a Phosphorylation Defect in the Transactivation Domain and Familial Insulinomatosis

SIMPLE SUMMARY: Adult-onset familial insulinomatosis is a rare disorder with recurrent, severe hypoglycemia caused by multiple insulin-secreting pancreatic tumors. The etiology was unclear until the genetic variant p.Ser64Phe in the MAFA protein, a key coordinator of insulin secretion in pancreatic cells, was defined as the cause in two families. Based on the cases of two sisters with insulinomatosis, we aimed to identify further disease causes. The sequencing of the complete coding regions of the patients’ genomes revealed a second genetic MAFA variant, p.Thr57Arg, as the cause of familial insulinomatosis, linking genetic, clinical, and biochemical analyses from the patients’ family to the pre-described cell culture data. Thus, we confirm a defect in a crucial regulatory region of the MAFA protein as an important cause of a specific hereditary syndrome, which is characterized by insulinomatosis and/or mild hyperglycemia. This study extends the pathophysiological and diagnostic disease concept and verifies the inheritance pattern of familial insulinomatosis. ABSTRACT: Adult-onset familial insulinomatosis is a rare disorder with recurrent, severe hypoglycemia caused by multiple insulin-secreting pancreatic tumors. The etiology was unclear until the variant p.Ser64Phe in the transcription factor MAFA, a key coordinator of β-cell insulin secretion, was defined as the cause in two families. We here describe detailed genetic, clinical, and family analyses of two sisters with insulinomatosis, aiming to identify further disease causes. Using exome sequencing, we detected a novel, heterozygous missense variant, p.Thr57Arg, in MAFA’s highly conserved transactivation domain. The impact of the affected region is so crucial that in vitro expression studies replacing Thr57 have already been performed, demonstrating a phosphorylation defect with the impairment of transactivation activity and degradation. However, prior to our study, the link to human disease was missing. Furthermore, mild hyperglycemia was observed in six additional, heterozygote family members, indicating that not only insulinomatosis but also MODY-like symptoms co-segregate with p.Thr57Arg. The pre-described MAFA variant, p.Ser64Phe, is located in the same domain, impairs the same phosphorylation cascade, and results in the same symptoms. We confirm MAFA phosphorylation defects are important causes of a characteristic syndrome, thus complementing the pathophysiological and diagnostic disease concept. Additionally, we verify the high penetrance and autosomal dominant inheritance pattern.