Mouse model implicates GNB3 duplication in a childhood obesity syndrome

Ian S. Goldlust; Karen E. Hermetz; Lisa M. Catalano; Richard T. Barfield; Rebecca Cozad; Grace Wynn; Alev Cagla Ozdemir; Karen N. Conneely; Jennifer G. Mulle; Shikha Dharamrup; Madhuri R. Hegde; Katherine H. Kim; Brad Angle; Alison Colley; Amy E. Webb; Erik C. Thorland; Jay W. Ellison; Jill A. Rosenfeld; Blake C. Ballif; Lisa G. Shaffer; Laurie A. Demmer; Beverly A. Searle; Sarah L. Wynn; M. Katharine Rudd

doi:10.1073/pnas.1305999110

Mouse model implicates GNB3 duplication in a childhood obesity syndrome

Ian S. Goldlust, Karen E. Hermetz, Lisa M. Catalano, Richard T. Barfield, Rebecca Cozad, Grace Wynn, Alev Cagla Ozdemir, Karen N. Conneely, Jennifer G. Mulle, Shikha Dharamrup, Madhuri R. Hegde, Katherine H. Kim, Brad Angle, Alison Colley, Amy E. Webb, Erik C. Thorland, Jay W. Ellison, Jill A. Rosenfeld, Blake C. Ballif, Lisa G. ShafferLaurie A. Demmer, Beverly A. Searle, Sarah L. Wynn, M. Katharine Rudd

Laboratory Medicine and Pathology

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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.

Original language	English (US)
Pages (from-to)	14990-14994
Number of pages	5
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	110
Issue number	37
DOIs	https://doi.org/10.1073/pnas.1305999110
State	Published - Sep 10 2013

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Goldlust, I. S., Hermetz, K. E., Catalano, L. M., Barfield, R. T., Cozad, R., Wynn, G., Ozdemir, A. C., Conneely, K. N., Mulle, J. G., Dharamrup, S., Hegde, M. R., Kim, K. H., Angle, B., Colley, A., Webb, A. E., Thorland, E. C., Ellison, J. W., Rosenfeld, J. A., Ballif, B. C., ... Rudd, M. K. (2013). Mouse model implicates GNB3 duplication in a childhood obesity syndrome. Proceedings of the National Academy of Sciences of the United States of America, 110(37), 14990-14994. https://doi.org/10.1073/pnas.1305999110

Goldlust, IS, Hermetz, KE, Catalano, LM, Barfield, RT, Cozad, R, Wynn, G, Ozdemir, AC, Conneely, KN, Mulle, JG, Dharamrup, S, Hegde, MR, Kim, KH, Angle, B, Colley, A, Webb, AE, Thorland, EC, Ellison, JW, Rosenfeld, JA, Ballif, BC, Shaffer, LG, Demmer, LA, Searle, BA, Wynn, SL & Rudd, MK 2013, 'Mouse model implicates GNB3 duplication in a childhood obesity syndrome', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 37, pp. 14990-14994. https://doi.org/10.1073/pnas.1305999110

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title = "Mouse model implicates GNB3 duplication in a childhood obesity syndrome",

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.",

author = "Goldlust, {Ian S.} and Hermetz, {Karen E.} and Catalano, {Lisa M.} and Barfield, {Richard T.} and Rebecca Cozad and Grace Wynn and Ozdemir, {Alev Cagla} and Conneely, {Karen N.} and Mulle, {Jennifer G.} and Shikha Dharamrup and Hegde, {Madhuri R.} and Kim, {Katherine H.} and Brad Angle and Alison Colley and Webb, {Amy E.} and Thorland, {Erik C.} and Ellison, {Jay W.} and Rosenfeld, {Jill A.} and Ballif, {Blake C.} and Shaffer, {Lisa G.} and Demmer, {Laurie A.} and Searle, {Beverly A.} and Wynn, {Sarah L.} and Rudd, {M. Katharine}",

note = "Funding Information: The authors are grateful to acknowledge the financial supported by the ?Strategic Priority Research Program? of Chinese Academy of Sciences, Grant No. XD02002400, Youth Innovation Promotion Association CAS and the National Natural Science Foundation of China (21406256).",

year = "2013",

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doi = "10.1073/pnas.1305999110",

language = "English (US)",

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AU - Goldlust, Ian S.

AU - Hermetz, Karen E.

AU - Catalano, Lisa M.

AU - Barfield, Richard T.

AU - Cozad, Rebecca

AU - Wynn, Grace

AU - Ozdemir, Alev Cagla

AU - Conneely, Karen N.

AU - Mulle, Jennifer G.

AU - Dharamrup, Shikha

AU - Hegde, Madhuri R.

AU - Kim, Katherine H.

AU - Angle, Brad

AU - Colley, Alison

AU - Webb, Amy E.

AU - Thorland, Erik C.

AU - Ellison, Jay W.

AU - Rosenfeld, Jill A.

AU - Ballif, Blake C.

AU - Shaffer, Lisa G.

AU - Demmer, Laurie A.

AU - Searle, Beverly A.

AU - Wynn, Sarah L.

AU - Rudd, M. Katharine

N1 - Funding Information: The authors are grateful to acknowledge the financial supported by the ?Strategic Priority Research Program? of Chinese Academy of Sciences, Grant No. XD02002400, Youth Innovation Promotion Association CAS and the National Natural Science Foundation of China (21406256).

PY - 2013/9/10

Y1 - 2013/9/10

N2 - 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.

AB - 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.

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Mouse model implicates GNB3 duplication in a childhood obesity syndrome

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