Human SH2B1 Mutations Are Associated With Maladaptive Behaviors and Obesity

J Clin Invest. 2012 Dec;122(12):4732-6. doi: 10.1172/JCI62696. Epub 2012 Nov 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Adult
  • Aggression
  • Base Sequence
  • Case-Control Studies
  • Cell Movement
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Energy Intake / genetics
  • Female
  • Frameshift Mutation*
  • Genetic Association Studies
  • HEK293 Cells
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Obesity / genetics*
  • Phenotype
  • Protein Transport
  • Social Isolation
  • Young Adult

Substances

  • Adaptor Proteins, Signal Transducing
  • SH2B1 protein, human