Human SH2B1 mutations are associated with maladaptive behaviors and obesity
Michael E. Doche, … , Christin Carter-Su, I. Sadaf Farooqi
Michael E. Doche, … , Christin Carter-Su, I. Sadaf Farooqi
Published November 19, 2012
Citation Information: J Clin Invest. 2012;122(12):4732-4736. https://doi.org/10.1172/JCI62696.
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Human SH2B1 mutations are associated with maladaptive behaviors and obesity

Abstract

Src homology 2 B adapter protein 1 (SH2B1) modulates signaling by a variety of ligands that bind to receptor tyrosine kinases or JAK-associated cytokine receptors, including leptin, insulin, growth hormone (GH), and nerve growth factor (NGF). Targeted deletion of Sh2b1 in mice results in increased food intake, obesity, and insulin resistance, with an intermediate phenotype seen in heterozygous null mice on a high-fat diet. We identified SH2B1 loss-of-function mutations in a large cohort of patients with severe early-onset obesity. Mutation carriers exhibited hyperphagia, childhood-onset obesity, disproportionate insulin resistance, and reduced final height as adults. Unexpectedly, mutation carriers exhibited a spectrum of behavioral abnormalities that were not reported in controls, including social isolation and aggression. We conclude that SH2B1 plays a critical role in the control of human food intake and body weight and is implicated in maladaptive human behavior.

Authors

Michael E. Doche, Elena G. Bochukova, Hsiao-Wen Su, Laura R. Pearce, Julia M. Keogh, Elana Henning, Joel M. Cline, Anne Dale, Tim Cheetham, Inês Barroso, Lawrence S. Argetsinger, Stephen O’Rahilly, Liangyou Rui, Christin Carter-Su, I. Sadaf Farooqi

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Figure 3

Subcellular distribution of SH2B1β WT and mutant proteins.

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Subcellular distribution of SH2B1β WT and mutant proteins. Live 293T cel...
Live 293T cells transiently expressing GFP-tagged WT, P90H, A175N, P322S, or F344LfsX20 SH2B1β were stained with the plasma membrane marker wheat germ agglutinin Alexa Fluor 594 (red) and imaged using confocal fluorescence microscopy. Shown are GFP fluorescence alone (green; top) and overlay of GFP and plasma membrane marker (bottom). Scale bars: 10 μm. Below, green and red signal intensity along the yellow arrows was determined using MetaVue Linescan. Arrows (red signal intensity peak) indicate position of the plasma membrane on the linescan. Horizontal lines on the linescan graphs denote the plasma membrane and cytoplasm values used to determine the plasma membrane/cytoplasm green signal intensity ratios (means ± SEM). The SH2B1β truncation mutant localized to the PM to a lesser extent than did SH2B1β WT. *P < 0.0001 vs. WT.