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dc.contributor.authorKaci, Alba
dc.contributor.authorSolheim, Marie Holm
dc.contributor.authorSilgjerd, Trine
dc.contributor.authorHjaltadottir, Jorunn
dc.contributor.authorHornnes, Lorentze Hope
dc.contributor.authorMolnes, Janne
dc.contributor.authorMadsen, Andre Greger
dc.contributor.authorSjøholt, Gry
dc.contributor.authorBellanne-Chantelot, Christine
dc.contributor.authorCaswell, Richard
dc.contributor.authorSagen, Jørn Vegard
dc.contributor.authorNjølstad, Pål Rasmus
dc.contributor.authorAukrust, Ingvild
dc.contributor.authorBjørkhaug, Lise
dc.date.accessioned2024-08-06T11:37:25Z
dc.date.available2024-08-06T11:37:25Z
dc.date.created2024-03-05T08:02:19Z
dc.date.issued2024
dc.identifier.issn0964-6906
dc.identifier.urihttps://hdl.handle.net/11250/3144713
dc.description.abstractHepatocyte nuclear factor-4 alpha (HNF-4A) regulates genes with roles in glucose metabolism and β-cell development. Although pathogenic HNF4A variants are commonly associated with maturity-onset diabetes of the young (MODY1; HNF4A-MODY), rare phenotypes also include hyperinsulinemic hypoglycemia, renal Fanconi syndrome and liver disease. While the association of rare functionally damaging HNF1A variants with HNF1A-MODY and type 2 diabetes is well established owing to robust functional assays, the impact of HNF4A variants on HNF-4A transactivation in tissues including the liver and kidney is less known, due to lack of similar assays. Our aim was to investigate the functional effects of seven HNF4A variants, located in the HNF-4A DNA binding domain and associated with different clinical phenotypes, by various functional assays and cell lines (transactivation, DNA binding, protein expression, nuclear localization) and in silico protein structure analyses. Variants R85W, S87N and R89W demonstrated reduced DNA binding to the consensus HNF-4A binding elements in the HNF1A promoter (35, 13 and 9%, respectively) and the G6PC promoter (R85W ~10%). While reduced transactivation on the G6PC promoter in HepG2 cells was shown for S87N (33%), R89W (65%) and R136W (35%), increased transactivation by R85W and R85Q was confirmed using several combinations of target promoters and cell lines. R89W showed reduced nuclear levels. In silico analyses supported variant induced structural impact. Our study indicates that cell line specific functional investigations are important to better understand HNF4A-MODY genotype–phenotype correlations, as our data supports ACMG/AMP interpretations of loss-of-function variants and propose assay-specific HNF4A control variants for future functional investigations.en_US
dc.language.isoengen_US
dc.publisherOxford University Pressen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.titleFunctional characterization of HNF4A gene variants identify promoter and cell line specific transactivation effectsen_US
dc.typeJournal articleen_US
dc.typePeer revieweden_US
dc.description.versionpublishedVersionen_US
dc.rights.holderCopyright 2024 The Author(s)en_US
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode2
dc.identifier.doihttps://doi.org/10.1093/hmg/ddae027
dc.identifier.cristin2251997
dc.source.journalHuman Molecular Geneticsen_US
dc.source.pagenumber894–904en_US
dc.identifier.citationHuman Molecular Genetics. 2024, 33 (10), 894–904.en_US
dc.source.volume33en_US
dc.source.issue10en_US


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Navngivelse 4.0 Internasjonal
Except where otherwise noted, this item's license is described as Navngivelse 4.0 Internasjonal