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Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.

dc.rights.licenseopenen_US
dc.contributor.authorSCHÖNAUER, Ria
dc.contributor.authorJIN, Wenjun
dc.contributor.authorFINDEISEN, Christin
dc.contributor.authorVALENZUELA, Irene
dc.contributor.authorDEVLIN, Laura Alice
dc.contributor.authorMURRELL, Jill
dc.contributor.authorBEDOUKIAN, Emma C
dc.contributor.authorPÖSCHLA, Linda
dc.contributor.authorHANTMANN, Elena
dc.contributor.authorRIEDHAMMER, Korbinian M
dc.contributor.authorHOEFELE, Julia
dc.contributor.authorPLATZER, Konrad
dc.contributor.authorBIEMANN, Ronald
dc.contributor.authorCAMPEAU, Philipp M
dc.contributor.authorMÜNCH, Johannes
dc.contributor.authorHEYNE, Henrike
dc.contributor.authorHOFFMANN, Anne
dc.contributor.authorGHOSH, Adhideb
dc.contributor.authorSUN, Wenfei
dc.contributor.authorDONG, Hua
dc.contributor.authorNOÉ, Falko
dc.contributor.authorWOLFRUM, Christian
dc.contributor.authorWOODS, Emily
dc.contributor.authorPARKER, Michael J
dc.contributor.authorNEATU, Ruxandra
dc.contributor.authorLE GUYADER, Gwenael
dc.contributor.authorBRUEL, Ange-Line
dc.contributor.authorPERRIN, Laurence
dc.contributor.authorSPIEWAK, Helena
dc.contributor.authorMISSOTTE, Isabelle
dc.contributor.authorFOURGEAUD, Melanie
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorMICHAUD, Vincent
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorLACOMBE, Didier
dc.contributor.authorPAOLUCCI, Sarah A
dc.contributor.authorBUCHAN, Jillian G
dc.contributor.authorGLISSMEYER, Margaret
dc.contributor.authorPOPP, Bernt
dc.contributor.authorBLÜHER, Matthias
dc.contributor.authorSAYER, John A
dc.contributor.authorHALBRITTER, Jan
dc.date.accessioned2023-11-28T14:13:13Z
dc.date.available2023-11-28T14:13:13Z
dc.date.issued2023-06-01
dc.identifier.issn1537-6605en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/186202
dc.description.abstractEnWhile common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.
dc.language.isoENen_US
dc.subject6q16.1 microdeletion
dc.subjectBRN2
dc.subjectPOU3F2
dc.subjectPrader-Willi-like syndrome
dc.subjectAutism
dc.subjectHyperphagia
dc.subjectNeurodevelopmental delay
dc.subjectObesity
dc.title.enMonoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
dc.title.alternativeAm J Hum Geneten_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1016/j.ajhg.2023.04.010en_US
dc.subject.halSciences du Vivant [q-bio]/Génétiqueen_US
dc.identifier.pubmed37207645en_US
bordeaux.journalAmerican Journal of Human Geneticsen_US
bordeaux.page998-1007en_US
bordeaux.volume110en_US
bordeaux.hal.laboratoriesMaladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211en_US
bordeaux.issue6en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.identifierhal-04312305
hal.version1
hal.date.transferred2023-11-28T14:13:17Z
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exporttrue
workflow.import.sourcepubmed
dc.rights.ccPas de Licence CCen_US
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