Fottner Christian, Sollfrank Stefanie, Ghiasi Mursal, Adenaeuer Anke, Musholt Thomas, Schad Arno, Miederer Matthias, Schadmand-Fischer Simin, Weber Matthias M, Lackner Karl J, Rossmann Heidi
Department of Endocrinology and Metabolism, I Medical Clinic, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Cancers (Basel). 2022 Apr 1;14(7):1798. doi: 10.3390/cancers14071798.
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.
成人起病型家族性胰岛素瘤病是一种罕见的疾病，由多个分泌胰岛素的胰腺肿瘤引起反复严重低血糖。在转录因子MAFA（β细胞胰岛素分泌的关键协调因子）中的p.Ser64Phe变异被确定为两个家族的病因之前，其病因尚不清楚。我们在此描述了两名患有胰岛素瘤病姐妹的详细基因、临床和家族分析，旨在确定更多的疾病病因。通过外显子组测序，我们在MAFA高度保守的反式激活结构域中检测到一个新的杂合错义变异p.Thr57Arg。受影响区域的影响至关重要，以至于已经进行了体外表达研究来替代Thr57，结果显示存在磷酸化缺陷，反式激活活性受损且发生降解。然而，在我们的研究之前，与人类疾病并无关联。此外，在另外六名杂合子家族成员中观察到轻度高血糖，这表明不仅胰岛素瘤病，而且类似青年发病型成年糖尿病（MODY）的症状也与p.Thr57Arg共分离。先前描述的MAFA变异p.Ser64Phe位于同一结构域，损害相同的磷酸化级联反应，并导致相同的症状。我们证实MAFA磷酸化缺陷是一种特征性综合征的重要病因，从而补充了病理生理和诊断性疾病概念。此外，我们验证了高外显率和常染色体显性遗传模式。
