Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-7026
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 |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-7026 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
Document type specification: | Scientific article |
License: | CC BY |
Information on rights of use: | https://creativecommons.org/licenses/by/4.0/ |
Journal: | Cancers 14 7 |
Pages or article number: | 1798 |
Publisher: | MDPI |
Publisher place: | Basel |
Issue date: | 2022 |
ISSN: | 2072-6694 |
Publisher URL: | https://doi.org/10.3390/cancers14071798 |
Publisher DOI: | 10.3390/cancers14071798 |
Appears in collections: | DFG-491381577-G |
Files in This Item:
File | Description | Size | Format | ||
---|---|---|---|---|---|
![]() | second_mafa_variant_causing_a-20220523104508147.pdf | 3.93 MB | Adobe PDF | View/Open |