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American Society for Clinical Investigation, Journal of Clinical Investigation, 12(122), p. 4732-4736

DOI: 10.1172/jci62696

American Society for Clinical Investigation, Journal of Clinical Investigation, 1(123), p. 526-526

DOI: 10.1172/jci68022

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Human SH2B1 mutations are associated with maladaptive behaviors and obesity

Journal article published in 2012 by Michael E. Doche, Elena G. Bochukova, Hsiao-Wen Su, Laura R. Pearce, Julia M. Keogh, Elana Henning, Joel M. Cline, Sadia Saeed, Anne Dale, Tim Cheetham, Inês Barroso, Lawrence S. Argetsinger, Stephen O’Rahilly, Liangyou Rui, Christin Carter-Su and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.