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Human SH2B1 mutations are associated with maladaptive behaviors and obesity

Lookup NU author(s): Professor Timothy Cheetham


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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.

Publication metadata

Author(s): Doche ME, Bochukova EG, Su HW, Pearce LR, Keogh JM, Henning E, Cline JM, Dale A, Cheetham T, Barroso I, Argetsinger LS, O'Rahilly S, Rui LY, Carter-Su C, Farooqi IS

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2012

Volume: 122

Issue: 12

Pages: 4732-4736

Print publication date: 03/12/2012

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation


DOI: 10.1172/JCI62696


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Funder referenceFunder name
Medical Research Council
NIHR Cam bridge Biomedical Research Centre
077016/Z/05/ZWellcorne Trust
082390/Z/07/ZWellcorne Trust
NIH-T32-GM008322Systems and Integrative Biology Training Grant
P30-CA46592University of Michigan Comprehensive Cancer Center (NIH)