Functional analyses of SH2B1 mutations with relevance for body weight regulation

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Heritability for the variance of body weight is high. Genome-wide association studies (GWAS) identified 98 genomic regions that are relevant for weight regulation (Speliotes et al. 2010, Bradfield et al. 2012, Berndt et al. 2012). As the first group world-wide we conducted a GWAS in 705 obesity trios comprising an extremely obese index patient with both biological parents (Scherag et al., 2010). In these families, we observed over-transmission of the obesity risk allele at the SH2B1 (Src-homology 2B adaptor protein 1 gene) locus to extremely obese children. SH2B1 is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity (rs7359397) or coding region (rs7498665, Thr484Ala) of the gene (e.g. Speliotes et al. Nat Genet 2010). Animal knockout models showed a relevance for human body weight regulation, as the murine model is obese, hyperphagic, hyperlipidemic, leptin and insulin resistant, hyperglycaemic, and glucose intolerant. In a mutation screen of the coding region of SH2B1 in extremely obese children and adolescents that contributed to the intial transmission disequilibrium, we detected a mutation that leads to amino acid exchanges in two splice variants of the gene (betaThr656Ile/gammaPro674Ser). This rare mutation was detected only in three individuals among 11,406 overweight and obese cases but not in 4,568 normal or underweight controls. Although in silico analyses predicted a potential functional effect of this variant, in vitro studies of leptin signaling showed no significant difference to the wildtype variant of SH2B1. The common polymorphism rs7498665 (Thr484Ala) which is association to obesity showed also no functional influence on leptin signaling.Here we will analyze the functional effect of non-synonymous variants in the obesity gene SH2B1. Of the currently known variants nine were chosen that affect different functional domains of SH2B1.These SH2B1 variants will be analyzed for their impact on leptin- and insulin receptor signalling. These two pathways are the main regulators of energy homeostasis in which SH2B1 enhances signaling. In addition, we will analyze the impact of the variants on SH2B1 protein expression.