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Schönauer, R.* ; Jin, W.* ; Findeisen, C.* ; Valenzuela, I.* ; Devlin, L.A.* ; Murrell, J.* ; Bedoukian, E.C.* ; Pöschla, L.* ; Hantmann, E.* ; Riedhammer, K.M.* ; Hoefele, J.* ; Platzer, K.* ; Biemann, R.* ; Campeau, P.M.* ; Münch, J.* ; Heyne, H.* ; Hoffmann, A. ; Ghosh, A.* ; Sun, W.* ; Dong, H.* ; Noé, F.* ; Wolfrum, C.* ; Woods, E.* ; Parker, M.J.* ; Neatu, R.* ; Le Guyader, G.* ; Bruel, A.L.* ; Perrin, L.* ; Spiewak, H.* ; Missotte, I.* ; Fourgeaud, M.* ; Michaud, V.* ; Lacombe, D.* ; Paolucci, S.A.* ; Buchan, J.G.* ; Glissmeyer, M.* ; Popp, B.* ; Blüher, M. ; Sayer, J.A.* ; Halbritter, J.*

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

Am. J. Hum. Genet. 110, 998-1007 (2023)
Publ. Version/Full Text DOI PMC
While 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords 6q16.1 Microdeletion ; Brn2 ; Pou3f2 ; Prader-willi-like Syndrome ; Autism ; Hyperphagia ; Neurodevelopmental Delay ; Obesity; Frameshift Mutation; Mc4r Agonist; Leptin; Setmelanotide; Protein; Sim1
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 110, Issue: 6, Pages: 998-1007 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Grants Medical Research Council
Cancer Research UK
Wellcome Trust
Department of Health