Gutenberg Open Science: Second MAFA variant causing a phosphorylation defect in the transactivation domain and familial insulinomatosis

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-7026

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DC Field	Value	Language
dc.contributor.author	Fottner, Christian	-
dc.contributor.author	Sollfrank, Stefanie	-
dc.contributor.author	Ghiasi, Mursal	-
dc.contributor.author	Adenaeuer, Anke	-
dc.contributor.author	Musholt, Thomas	-
dc.contributor.author	Schad, Arno	-
dc.contributor.author	Miederer, Matthias	-
dc.contributor.author	Schadmand-Fischer, Simin	-
dc.contributor.author	Weber, Matthias M.	-
dc.contributor.author	Lackner, Karl J.	-
dc.contributor.author	Rossmann, Heidi	-
dc.date.accessioned	2022-12-20T11:25:12Z	-
dc.date.available	2022-12-20T11:25:12Z	-
dc.date.issued	2022	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/7040	-
dc.description.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.	en_GB
dc.description.sponsorship	Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577	de
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	610 Medizin	de_DE
dc.subject.ddc	610 Medical sciences	en_GB
dc.title	Second MAFA variant causing a phosphorylation defect in the transactivation domain and familial insulinomatosis	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-7026	-
jgu.type.contenttype	Scientific article	de
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 04 Medizin	de
jgu.organisation.number	2700	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Cancers	de
jgu.journal.volume	14	de
jgu.journal.issue	7	de
jgu.pages.alternative	1798	de
jgu.publisher.year	2022	-
jgu.publisher.name	MDPI	de
jgu.publisher.place	Basel	de
jgu.publisher.uri	https://doi.org/10.3390/cancers14071798	de
jgu.publisher.issn	2072-6694	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	610	de
jgu.publisher.doi	10.3390/cancers14071798	de
jgu.organisation.ror	https://ror.org/023b0x485	-
jgu.subject.dfg	Lebenswissenschaften	de
Appears in collections:	DFG-491381577-G

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