Title: Mouse model implicates GNB3 duplication in a childhood obesity syndrome.
Authors: Goldlust, Ian S; Hermetz, Karen E; Catalano, Lisa M; Barfield, Richard T; Cozad, Rebecca; Wynn, Grace; Ozdemir, Alev Cagla; Conneely, Karen N; Mulle, Jennifer G; Dharamrup, Shikha; Hegde, Madhuri R; Kim, Katherine H; Angle, Brad; Colley, Alison; Webb, Amy E; Thorland, Erik C; Ellison, Jay W; Rosenfeld, Jill A; Ballif, Blake C; Shaffer, Lisa G; Demmer, Laurie A; Unique Rare Chromosome Disorder Support Group; Rudd, M Katharine
Published In Proc Natl Acad Sci U S A, (2013 Sep 10)
Abstract: Obesity is a highly heritable condition and a risk factor for other diseases, including type 2 diabetes, cardiovascular disease, hypertension, and cancer. Recently, genomic copy number variation (CNV) has been implicated in cases of early onset obesity that may be comorbid with intellectual disability. Here, we describe a recurrent CNV that causes a syndrome associated with intellectual disability, seizures, macrocephaly, and obesity. This unbalanced chromosome translocation leads to duplication of over 100 genes on chromosome 12, including the obesity candidate gene G protein β3 (GNB3). We generated a transgenic mouse model that carries an extra copy of GNB3, weighs significantly more than its wild-type littermates, and has excess intraabdominal fat accumulation. GNB3 is highly expressed in the brain, consistent with G-protein signaling involved in satiety and/or metabolism. These functional data connect GNB3 duplication and overexpression to elevated body mass index and provide evidence for a genetic syndrome caused by a recurrent CNV.
PubMed ID: 23980137
MeSH Terms: Adolescent; Adult; Animals; Brain/metabolism; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 12/genetics; Chromosomes, Human, Pair 8/genetics; Disease Models, Animal; Female; GTP-Binding Proteins/metabolism; Gene Duplication*; Heterotrimeric GTP-Binding Proteins/genetics*; Heterotrimeric GTP-Binding Proteins/metabolism; Humans; Male; Mice; Mice, Transgenic; Pediatric Obesity/genetics*; Pediatric Obesity/metabolism; Pediatric Obesity/pathology; Pedigree; Syndrome; Translocation, Genetic