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Volckmar, A.-L.* ; Bolze, F.* ; Jarick, I.* ; Knoll, N.* ; Scherag, A.* ; Reinehr, T.* ; Illig, T. ; Grallert, H. ; Wichmann, H.-E. ; Wiegand, S.* ; Biebermann, H.* ; Krude, H.* ; Fischer-Posovszky, P.* ; Rief, W.* ; Wabitsch, M.* ; Klingenspor, M.* ; Hebebrand, J.* ; Hinney, A.*

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

BMC Med. Genomics 5:65 (2012)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords SH2B1; Obesity; BMI; rs7498665; Mutation screen
Language english
Publication Year 2012
HGF-reported in Year 2013
e-ISSN 1755-8794
Journal BMC Medical Genomics
Quellenangaben Volume: 5, Issue: , Pages: , Article Number: 65 Supplement: ,
Publisher BioMed Central
Reviewing status Peer reviewed
Institute(s) Research Unit Molecular Epidemiology (AME)
Institute of Epidemiology (EPI)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504200-002
G-503900-002
PubMed ID 23270367
DOI 10.1186/1755-8794-5-65
Scopus ID 84871570099
Erfassungsdatum 2013-03-04
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