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Authors: 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
Title: Second MAFA variant causing a phosphorylation defect in the transactivation domain and familial insulinomatosis
Online publication date: 20-Dec-2022
Year of first publication: 2022
Language: english
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.
DDC: 610 Medizin
610 Medical sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 04 Medizin
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
Document type specification: Scientific article
License: CC BY
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Journal: Cancers
Pages or article number: 1798
Publisher: MDPI
Publisher place: Basel
Issue date: 2022
ISSN: 2072-6694
Publisher URL:
Publisher DOI: 10.3390/cancers14071798
Appears in collections:DFG-491381577-G

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