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

Autor:	Schönauer R; Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany; Division of Nephrology, Endocrinology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany., Jin W; Division of Nephrology, Endocrinology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany., Findeisen C; Division of Nephrology, Endocrinology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany., Valenzuela I; Medical Genetics, Vall d'Hebron, Barcelona, Spain., Devlin LA; Translational and Clinical Research Institute, Newcastle University, Central Parkway, NE1 3BZ Newcastle, UK., Murrell J; Division of Genomic Diagnostics at Children's Hospital of Philadelphia, Philadelphia, PA, USA., Bedoukian EC; Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Pöschla L; Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany., Hantmann E; Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany., Riedhammer KM; Institute of Human Genetics, Klinikum rechts der Isar, Technical University Munich, School of Medicine, Munich, Germany; Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, School of Medicine, Munich, Germany., Hoefele J; Institute of Human Genetics, Klinikum rechts der Isar, Technical University Munich, School of Medicine, Munich, Germany., Platzer K; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Biemann R; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany., Campeau PM; Department of Pediatrics, University of Montreal, Montreal, QC, Canada., Münch J; Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany., Heyne H; Hasso-Plattner-Institute, University of Potsdam, Potsdam, Germany; Hasso Plattner Institute for Digital Health at Mount Sinai School of Medicine, New York City, NY, USA; Institute for Molecular Medicine Finland: FIMM, University of Helsinki, Helsinki, Finland., Hoffmann A; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany., Ghosh A; Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland., Sun W; Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland., Dong H; Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland., Noé F; Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland., Wolfrum C; Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland., Woods E; Sheffield Children's NHS Foundation Trust, Sheffield, UK., Parker MJ; Sheffield Children's NHS Foundation Trust, Sheffield, UK., Neatu R; Translational and Clinical Research Institute, Newcastle University, Central Parkway, NE1 3BZ Newcastle, UK., Le Guyader G; Unité neurovasculaire et troubles cognitifs, University of Poitiers, Poitiers, France., Bruel AL; Equipe GAD, UMR1231 Inserm, Université de Bourgogne Franche Comté, Dijon, France., Perrin L; UF de Génétique Clinique Département de Génétique, CHU Paris - Hôpital Robert Debré, Paris, France., Spiewak H; North East and Yorkshire Genomic Laboratory Hub, Central Laboratory, St. James's University Hospital, Leeds, UK., Missotte I; Service de Pédiatrie, Centre Hospitalier Territorial, Nouvelle Calédonie, France., Fourgeaud M; Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, CHU de Bordeaux, France., Michaud V; Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, CHU de Bordeaux, France; INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), Université de Bordeaux, Bordeaux, France., Lacombe D; Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, CHU de Bordeaux, France; INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), Université de Bordeaux, Bordeaux, France., Paolucci SA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Buchan JG; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Glissmeyer M; Seattle Children ́s Hospital, Seattle, WA, USA., Popp B; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Center of Functional Genomics, Berlin, Germany., Blüher M; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany., Sayer JA; Translational and Clinical Research Institute, Newcastle University, Central Parkway, NE1 3BZ Newcastle, UK; The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Road, NE7 7DN Newcastle, UK; NIHR Newcastle Biomedical Research Centre, NE4 5PL Newcastle, UK., Halbritter J; Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany; Division of Nephrology, Endocrinology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany. Electronic address: jan.halbritter@charite.de.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2023 Jun 01; Vol. 110 (6), pp. 998-1007. Date of Electronic Publication: 2023 May 18.
DOI:	10.1016/j.ajhg.2023.04.010
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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