학술논문
Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
Document Type
Article
Author
Schönauer, Ria; Jin, Wenjun; Findeisen, Christin; Valenzuela, Irene; Devlin, Laura Alice; Murrell, Jill; Bedoukian, Emma C.; Pöschla, Linda; Hantmann, Elena; Riedhammer, Korbinian M.; Hoefele, Julia; Platzer, Konrad; Biemann, Ronald; Campeau, Philipp M.; Münch, Johannes; Heyne, Henrike; Hoffmann, Anne; Ghosh, Adhideb; Sun, Wenfei; Dong, Hua
Source
Subject
*AUTISM spectrum disorders
*ADOLESCENT obesity
*OBESITY
*NEURAL development
*CENTRAL nervous system
*BODY mass index
*
*
*
*
*
Language
ISSN
0002-9297
Abstract
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. [Display omitted] Monogenic forms of obesity have taught us about central nervous system dysregulation of food intake as a disease mechanism. We associate ultra-rare variants in POU3F2 , encoding a central nervous system transcription factor, with syndromic obesity and neurodevelopmental delay in 12 individuals. Additionally, we demonstrate variant pathogenicity through in vitro analysis. [ABSTRACT FROM AUTHOR]