title: Mutation screen in the GWAS derived obesity gene SH2B1 including functional analyses of detected variants.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Child and Adolescent Psychiatry, University Duisburg-Essen, Virchowstr, 171, D 45147, Essen, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Volckmar
authors.forename: Florian
authors.initials: F
authors.lastname: Bolze
authors.forename: Ivonne
authors.initials: I
authors.lastname: Jarick
authors.forename: Nadja
authors.initials: N
authors.lastname: Knoll
authors.forename: André
authors.initials: A
authors.lastname: Scherag
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinehr
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.forename: Heinz-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Susanna
authors.initials: S
authors.lastname: Wiegand
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: Pamela
authors.initials: P
authors.lastname: Fischer-Posovszky
authors.forename: Winfried
authors.initials: W
authors.lastname: Rief
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D001665:Binding Sites / Q000235:genetics; D002648:Child; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006031:Glycosylation; D006801:Humans; D020738:Leptin / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D054411:Receptors, Leptin / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020738:Leptin; D022821:RNA Splice Sites; D054411:Receptors, Leptin; C518910:SH2B1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D008156:Luciferases