Mutation screen in the GWAS derived obesity gene SH2B1 including functional analyses of detected variants

BMC Medical Genomics

Anke Hinney^1,10  Johannes Hebebrand^1,10  Martin Klingenspor⁸  Martin Wabitsch³  Winfried Rief²  Pamela Fischer-Posovszky³  Heiko Krude⁷  Heike Biebermann⁷  Susanna Wiegand⁷  Heinz-Erich Wichmann⁵  Harald Grallert⁵  Thomas Illig⁴  Thomas Reinehr¹  André Scherag⁹  Nadja Knoll^1,10  Ivonne Jarick⁶  Florian Bolze⁸  Anna-Lena Volckmar^1,10 

[1] Vestische Children's Hospital Datteln, University of Witten/Herdecke, North Rhine-Westphalia, Germany;Division of Clinical Psychology, University of Marburg, Marburg, Germany;Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University of Ulm University Medical Center, Ulm, Germany;Hannover Unified Biobank, Hannover Medical School, Hannover, Germany;Institute of Epidemiology, Helmholtz-Zentrum, Munich, Germany;Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, Germany;Institute of Experimental Pediatric Endocrinology, Charité, Berlin, Germany;Molecular Nutritional Medicine, Else Kröner-Fresenius Center and Research Center for Nutrition and Food Science, Technical University Munich, München, Germany;Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany;Department of Child and Adolescent Psychiatry, University Duisburg-Essen, Virchowstr. 171, D 45147, Essen, Germany

关键词: Mutation screen;    rs7498665;    BMI;    Obesity;    SH2B1;   

Others  :  1121226
DOI  :  10.1186/1755-8794-5-65

 received in 2012-09-05, accepted in 2012-12-20,  发布年份 2012

【 摘 要 】

Background

The SH2B1 gene (Src-homology 2B adaptor protein 1 gene) is a solid candidate gene for obesity. Large scale GWAS studies depicted markers in the vicinity of the gene; animal models suggest a potential relevance for human body weight regulation.

Methods

We performed a mutation screen for variants in the SH2B1 coding sequence in 95 extremely obese children and adolescents. Detected variants were genotyped in independent childhood and adult study groups (up to 11,406 obese or overweight individuals and 4,568 controls). Functional implications on STAT3 mediated leptin signalling of the detected variants were analyzed in vitro.

Results

We identified two new rare mutations and five known SNPs (rs147094247, rs7498665, rs60604881, rs62037368 and rs62037369) in SH2B1. Mutation g.9483C/T leads to a non-synonymous, non-conservative exchange in the beta (βThr656Ile) and gamma (γPro674Ser) splice variants of SH2B1. It was additionally detected in two of 11,206 (extremely) obese or overweight children, adolescents and adults, but not in 4,506 population-based normal-weight or lean controls. The non-coding mutation g.10182C/A at the 3’ end of SH2B1 was only detected in three obese individuals. For the non-synonymous SNP rs7498665 (Thr484Ala) we observed nominal over-transmission of the previously described risk allele in 705 obesity trios (nominal p = 0.009, OR = 1.23) and an increased frequency of the same allele in 359 cases compared to 429 controls (nominal p = 0.042, OR = 1.23). The obesity risk-alleles at Thr484Ala and βThr656Ile/γPro674Ser had no effect on STAT3 mediated leptin receptor signalling in splice variants β and γ.

Conclusion

The rare coding mutation βThr656Ile/γPro674Ser (g.9483C/T) in SH2B1 was exclusively detected in overweight or obese individuals. Functional analyzes did not reveal impairments in leptin signalling for the mutated SH2B1.

【 授权许可】

   
2012 Volckmar et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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