Author contributions: I.S.G., K.E.H., and M.K.R. designed research; I.S.G., K.E.H., R.C., G.W., A.C.O., and S.D. performed research; I.S.G., K.E.H., L.M.C., R.T.B., G.W., A.C.O., K.N.C., J.G.M., M.R.H., K.H.K., B.A., A.C., A.E.W., E.C.T., J.W.E., J.A.R., B.C.B., L.G.S., L.A.D., U.R.C.D.S.G., and M.K.R. analyzed data; I.S.G. and M.K.R. wrote the paper; and L.M.C., K.H.K., B.A., A.C., A.E.W., E.C.T., J.W.E., J.A.R., B.C.B., L.G.S., L.A.D., U.R.C.D.S.G., and M.K.R. recruited and clinically assessed subjects.

^{Present address: Paw Print Genetics, Genetic Veterinary Sciences, Inc., Spokane, WA 99202.}

^{Present address: Division of Genetics, Levine Children's Hospital at Carolinas Medical Center, Charlotte, NC 28232.}

Edited^* by Stephen T. Warren, Emory University School of Medicine, Atlanta, GA, and approved July 29, 2013 (received for review March 29, 2013)

Significance

We describe a genomic disorder that causes obesity, intellectual disability, and seizures. Children with this syndrome carry an unbalanced chromosome translocation that results in the duplication of over 100 genes, including G protein β3 (GNB3). Although GNB3 polymorphisms have been associated with obesity, hypertension, and diabetes, the mechanism of GNB3 pathogenesis is unknown. We created a transgenic mouse model that carries a duplication of GNB3, weighs significantly more than wild-type mice, and has excess abdominal fat. GNB3 is highly expressed in the brain and may be important for signaling related to satiety and/or metabolism.

Significance

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.

Abstract

Body weight exhibits a heritability of ∼70% (1 –3), with both rare and common alleles contributing to obesity. Few cases of obesity are explained by mutations in single genes, with most confined to the well-known leptin/melanocortin pathway (4, 5). Genome-wide association studies (GWASs) have identified alleles that confer a small risk for elevated body mass index (BMI) and other measures of obesity, and some common variants involve candidate genes that are highly expressed in the central nervous system (6 –9). However, the functional mechanism by which most GWAS loci contribute to obesity is unknown.

Recently, large deletions and duplications that represent copy number variation (CNV) have been linked to early onset obesity in children (10 –14). Rare CNVs have proven to be highly penetrant in familial and spontaneous cases of obesity that are sometimes concomitant with intellectual disability (ID) and/or other neurodevelopmental disorders. Rare but recurrent CNVs are particularly useful to pinpoint critical regions or candidate genes, because their shared genotype can be correlated with a common phenotype. For example, recurrent deletions of 16p11.2 are enriched in multiple obesity cohorts vs. controls (10 –12).

Mouse models have been instrumental in unraveling the genetic mechanisms and signaling pathways involved in obesity, which are critical for the development of therapeutics. Notably, ob/ob mutant mice that lack leptin are morbidly obese and exhibit other features, including hyperphagia, infertility, decreased immune function, and energy and body temperature dysfunction (15, 16). In humans, congenital leptin deficiency causes early onset hyperphagia, hypogonadism, impaired immunity, and severe obesity (17). For both ob/ob mice and leptin-deficient humans, leptin replacement ameliorates many of these symptoms (18 –20). Mouse models of other metabolic disorders have also proven insightful in teasing apart the physiological effects of genes involved in obesity (21 –24).

Here, we report a syndrome caused by a recurrent chromosomal translocation associated with obesity as well as ID, seizures, macrocephaly, and eczema. Moreover, we have recapitulated the obesity phenotype in a transgenic mouse model and identified the gene responsible for elevated weight gain. This CNV duplication causes a highly penetrant form of early onset obesity.

Listed are age at assessment, GNB3 genotype (Fig. S9 and Table S2), height, weight, BMI, head circumference (HC), and percentiles (%). Subject 1 is an adult; her measurements do not fall within childhood growth percentiles. Subjects exhibit features (+) including developmental delay (DD), seizure (S), hypotonia (H), dysmorphic features (DF), abnormal gait (G), poor coordination (PC), ocular problems (O), eczema (E), social personality (SP), and dental/palate abnormalities (DP). Features not formally evaluated (N) or not present (−) are indicated. Detailed clinical information is located in SI Materials and Methods.

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Acknowledgments

We thank the families for participating in this study. Helen Zhang and the Emory Transgenic Mouse Core generated transgenic animals, and the Emory Integrated Genomics Core performed qRT-PCR and BAC copy number experiments. We also thank Cheryl Strauss for editorial assistance. This project was supported by National Institutes of Mental Health Grant 5R01MH92902 (to M.K.R.) and the Emory Discovery Fund.

Acknowledgments

Footnotes

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

^{The Unique Rare Chromosome Disorder Support Group authors are Beverly A. Searle and Sarah L. Wynn.}

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1305999110/-/DCSupplemental.

Footnotes

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