Mouse model implicates GNB3 duplication in a childhood obesity syndrome

被引：26

作者：

Goldlust, Ian S. ^{[1
]}

Hermetz, Karen E. ^{[1
]}

Catalano, Lisa M. ^{[1
]}

Barfield, Richard T. ^{[2
]}

Cozad, Rebecca ^{[1
]}

Wynn, Grace ^{[1
]}

Ozdemir, Alev Cagla ^{[1
]}

Conneely, Karen N. ^{[1
,2
]}

Mulle, Jennifer G. ^{[1
,3
]}

Dharamrup, Shikha ^{[1
]}

Hegde, Madhuri R. ^{[1
]}

Kim, Katherine H. ^{[4
]}

Angle, Brad ^{[4
]}

Colley, Alison ^{[5
]}

Webb, Amy E. ^{[6
]}

Thorland, Erik C. ^{[7
]}

Ellison, Jay W. ^{[8
]}

Rosenfeld, Jill A. ^{[8
]}

Ballif, Blake C. ^{[8
]}

Shaffer, Lisa G. ^{[8
]}

Demmer, Laurie A. ^{[9
]}

Rudd, M. Katharine ^{[1
]}

机构：

[1] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA

[2] Emory Univ, Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA

[3] Emory Univ, Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA

[4] Northwestern Univ Feinberg, Sch Med, Div Genet, Chicago, IL 60614 USA

[5] Dept Clin Genet, Liverpool, NSW 1871, Australia

[6] Amy E Webb Pediat, Pismo Beach, CA 93449 USA

[7] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA

[8] PerkinElmer Inc, Signature Genom Labs, Spokane, WA 99207 USA

[9] Tufts Univ, Sch Med, Div Genet & Metab, Boston, MA 02111 USA

[10] Unique Rare Chromosome Disorder Support Grp, Surrey CR3 5GN, England

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 37期

关键词：

BODY-MASS INDEX; EARLY-ONSET OBESITY; CONGENITAL LEPTIN DEFICIENCY; WOLF-HIRSCHHORN-SYNDROME; COPY NUMBER VARIANTS; GENOME-WIDE; HOMOLOGOUS RECOMBINATION; DEVELOPMENTAL DELAY; TRISOMY; 12P; DELETIONS;

D O I：

10.1073/pnas.1305999110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 beta 3 (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.

引用

页码：14990 / 14994

页数：5

共 47 条

[1] Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity
Bachmann-Gagescu, Ruxandra
Mefford, Heather C.
Cowan, Charles
Glew, Gwen M.
Hing, Anne V.
Wallace, Stephanie
Bader, Patricia I.
Hamati, Aline
Reitnauer, Pamela J.
Smith, Rosemarie
Stockton, David W.
Muhle, Hiltrud
Helbig, Ingo
Eichler, Evan E.
Ballif, Blake C.
Rosenfeld, Jill
Tsuchiya, Karen D.
[J]. GENETICS IN MEDICINE, 2010, 12 (10) : 641 - 647
[2] Trisomy 12p and Monosomy 4p: Phenotype-Genotype Correlation
Benussi, Daniela Gambel
Costa, Paola
Zollino, Marcella
Murdolo, Marina
Petix, Vincenzo
Carrozzi, Marco
Pecile, Vanna
[J]. GENETIC TESTING AND MOLECULAR BIOMARKERS, 2009, 13 (02) : 199 - 204
[3] Investigation of Mendelian forms of obesity holds out the prospect of personalized medicine
Blakemore, Alexandra I. F.
Froguel, Philippe
[J]. YEAR IN HUMAN AND MEDICAL GENETICS: NEW TRENDS IN MENDELIAN GENETICS, 2010, 1214 : 180 - 189
[4] Large, rare chromosomal deletions associated with severe early-onset obesity
Bochukova, Elena G.
Huang, Ni
Keogh, Julia
Henning, Elana
Purmann, Carolin
Blaszczyk, Kasia
Saeed, Sadia
Hamilton-Shield, Julian
Clayton-Smith, Jill
O'Rahilly, Stephen
Hurles, Matthew E.
Farooqi, I. Sadaf
[J]. NATURE, 2010, 463 (7281) : 666 - 670
[5] A genome-wide association meta-analysis identifies new childhood obesity loci
Bradfield, Jonathan P.
Taal, H. Rob
Timpson, Nicholas J.
Scherag, Andre
Lecoeur, Cecile
Warrington, Nicole M.
Hypponen, Elina
Holst, Claus
Valcarcel, Beatriz
Thiering, Elisabeth
Salem, Rany M.
Schumacher, Fredrick R.
Cousminer, Diana L.
Sleiman, Patrick M. A.
Zhao, Jianhua
Berkowitz, Robert I.
Vimaleswaran, Karani S.
Jarick, Ivonne
Pennell, Craig E.
Evans, David M.
St Pourcain, Beate
Berry, Diane J.
Mook-Kanamori, Dennis O.
Hofman, Albert
Rivadeneira, Fernando
Uitterlinden, Andre G.
van Duijn, Cornelia M.
van der Valk, Ralf J. P.
de Jongste, Johan C.
Postma, Dirkje S.
Boomsma, Dorret I.
Gauderman, W. James
Hassanein, Mohamed T.
Lindgren, Cecilia M.
Magi, Reedik
Boreham, Colin A. G.
Neville, Charlotte E.
Moreno, Luis A.
Elliott, Paul
Pouta, Anneli
Hartikainen, Anna-Liisa
Li, Mingyao
Raitakari, Olli
Lehtimaki, Terho
Eriksson, Johan G.
Palotie, Aarno
Dallongeville, Jean
Das, Shikta
Deloukas, Panos
McMahon, George
[J]. NATURE GENETICS, 2012, 44 (05) : 526 - +
[6] Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome
Burns, Brooke
Schmidt, Kristie
Williams, Stephen R.
Kim, Sun
Girirajan, Santhosh
Elsea, Sarah H.
[J]. HUMAN MOLECULAR GENETICS, 2010, 19 (20) : 4026 - 4042
[7] Molecular Basis of Obesity: Current Status and Future Prospects
Choquet, Helene
Meyre, David
[J]. CURRENT GENOMICS, 2011, 12 (03) : 154 - 168
[8] OBESE AND DIABETES - 2 MUTANT-GENES CAUSING DIABETES-OBESITY SYNDROMES IN MICE
COLEMAN, DL
[J]. DIABETOLOGIA, 1978, 14 (03) : 141 - 148
[9] A copy number variation morbidity map of developmental delay
Cooper, Gregory M.
Coe, Bradley P.
Girirajan, Santhosh
Rosenfeld, Jill A.
Vu, Tiffany H.
Baker, Carl
Williams, Charles
Stalker, Heather
Hamid, Rizwan
Hannig, Vickie
Abdel-Hamid, Hoda
Bader, Patricia
McCracken, Elizabeth
Niyazov, Dmitriy
Leppig, Kathleen
Thiese, Heidi
Hummel, Marybeth
Alexander, Nora
Gorski, Jerome
Kussmann, Jennifer
Shashi, Vandana
Johnson, Krys
Rehder, Catherine
Ballif, Blake C.
Shaffer, Lisa G.
Eichler, Evan E.
[J]. NATURE GENETICS, 2011, 43 (09) : 838 - U44
[10] Leptin revisited: its mechanism of action and potential for treating diabetes
Coppari, Roberto
Bjorboek, Christian
[J]. NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (09) : 692 - 708

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