Human SH2B1 mutations are associated with maladaptive behaviors and obesity

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 m 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.