MAFA missense mutation causes familial insulinomatosis and diabetes mellitus.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620610
Title:
MAFA missense mutation causes familial insulinomatosis and diabetes mellitus.
Authors:
Iacovazzo, D.; Flanagan, S.E.; Walker, E.; Quezado, R.; de Sousa Barros, F. A.; Caswell, R.; Johnson, M. B.; Wakeling, M.; Brändle, M.; Guo, M.; Dang, M. N.; Gabrovska, P.; Niederle, B.; Christ, E.; Jenni, S.; Sipos, B.; Nieser, M.; Frilling, A.; Dhatariya, K.; Chanson, P.; de Herder, W. W.; Konukiewitz, B.; Klöppel, G.; Stein, R.; Korbonits, M.; Ellard, Sian ( 0000-0002-7620-5526 )
Abstract:
The β-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic MAFA mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four females). Four patients from the index family, including two homozygotes, had a history of congenital cataract and/or glaucoma. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in β-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in β-cell lines was enhanced compared with wild-type MAFA. In summary, the p.Ser64Phe missense MAFA mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity.
Citation:
MAFA missense mutation causes familial insulinomatosis and diabetes mellitus. 2018, 115 (5):1027-1032 Proc. Natl. Acad. Sci. U.S.A.
Publisher:
Proceedings of the National Academy of Sciences of the USA
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Issue Date:
30-Jan-2018
URI:
http://hdl.handle.net/11287/620610
DOI:
10.1073/pnas.1712262115
PubMed ID:
29339498
Additional Links:
http://www.pnas.org/cgi/pmidlookup?view=long&pmid=29339498
Note:
This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.
Type:
Journal Article
Language:
en
ISSN:
1091-6490
Appears in Collections:
Molecular Genetics; 2018 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorIacovazzo, D.en
dc.contributor.authorFlanagan, S.E.en
dc.contributor.authorWalker, E.en
dc.contributor.authorQuezado, R.en
dc.contributor.authorde Sousa Barros, F. A.en
dc.contributor.authorCaswell, R.en
dc.contributor.authorJohnson, M. B.en
dc.contributor.authorWakeling, M.en
dc.contributor.authorBrändle, M.en
dc.contributor.authorGuo, M.en
dc.contributor.authorDang, M. N.en
dc.contributor.authorGabrovska, P.en
dc.contributor.authorNiederle, B.en
dc.contributor.authorChrist, E.en
dc.contributor.authorJenni, S.en
dc.contributor.authorSipos, B.en
dc.contributor.authorNieser, M.en
dc.contributor.authorFrilling, A.en
dc.contributor.authorDhatariya, K.en
dc.contributor.authorChanson, P.en
dc.contributor.authorde Herder, W. W.en
dc.contributor.authorKonukiewitz, B.en
dc.contributor.authorKlöppel, G.en
dc.contributor.authorStein, R.en
dc.contributor.authorKorbonits, M.en
dc.contributor.authorEllard, Sianen
dc.date.accessioned2018-02-08T15:40:07Z-
dc.date.available2018-02-08T15:40:07Z-
dc.date.issued2018-01-30-
dc.identifier.citationMAFA missense mutation causes familial insulinomatosis and diabetes mellitus. 2018, 115 (5):1027-1032 Proc. Natl. Acad. Sci. U.S.A.en
dc.identifier.issn1091-6490-
dc.identifier.pmid29339498-
dc.identifier.doi10.1073/pnas.1712262115-
dc.identifier.urihttp://hdl.handle.net/11287/620610-
dc.description.abstractThe β-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic MAFA mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four females). Four patients from the index family, including two homozygotes, had a history of congenital cataract and/or glaucoma. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in β-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in β-cell lines was enhanced compared with wild-type MAFA. In summary, the p.Ser64Phe missense MAFA mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity.en
dc.language.isoenen
dc.publisherProceedings of the National Academy of Sciences of the USAen
dc.relation.urlhttp://www.pnas.org/cgi/pmidlookup?view=long&pmid=29339498en
dc.rightsArchived with thanks to Proceedings of the National Academy of Sciences of the United States of Americaen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleMAFA missense mutation causes familial insulinomatosis and diabetes mellitus.en
dc.typeJournal Articleen
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen
dc.description.noteThis article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.en
dc.type.versionPublisheden

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