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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Brief Report Metabolism

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 2

Functional characterization of SH2B1 mutations.

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Functional characterization of SH2B1 mutations. (A) PC12 cells transie...
(A) PC12 cells transiently expressing GFP-tagged WT or mutant SH2B1β were treated with NGF to induce differentiation. Percent differentiated values were normalized against WT at day 1 of differentiation (means ± SEM). All mutants impaired the rate of NGF-induced neuronal differentiation compared with WT. *P < 0.0001, 1-way ANOVA with Dunnett’s post-test. (B) 293T cells transiently expressing GFP-tagged WT or mutant SH2B1β were treated with or without leptomycin B (LMB) and imaged using confocal microscopy. Scale bars: 10 μm. All SH2B1β mutant proteins exhibited an impaired ability to accumulate in the nucleus (see Supplemental Figure 1). (C) RAW264.7 macrophages transiently expressing GFP-tagged WT or mutant SH2B1β were added to the upper chamber, and GH (500 ng/ml) to the lower chamber, of a Transwell plate. Average values for migrated cells were normalized to unstimulated control values (means ± SEM). All SH2B1β mutants inhibited GH-induced cell migration. *P < 0.05. (D) Flag-tagged SH2B1β was immunoprecipitated from HEK293 cells coexpressing Flag-tagged WT SH2B1β and GFP-tagged SH2B1β mutants (including the dimerization mutant 3AD/2FA). Immunoprecipitated proteins and proteins in cell lysates were immunoblotted using anti-Flag and anti-GFP antibodies. Binding of the P90H and A175N mutants was similar to that seen with WT; however, the P322S mutation enhanced dimerization. Note that for the A175N mutant, all experiments were performed using rat SH2B1β (NP_001041645), in which Thr175 is Ala175.