title: Genetic variance in the spinocerebellar ataxia type 2 (ATXN2) gene in children with severe early onset obesity.
abstract: BACKGROUND
  Expansion of a CAG repeat in the coding region of exon 1 in the ATXN2 gene located in human chromosome 12q24.1 causes the neurodegenerative disease spinocerebellar ataxia type 2 (SCA2). In contrast to other polyglutamine (polyQ) disorders, the SCA2 repeat is not highly polymorphic in central European (CEU) controls with Q22 representing 90% of alleles, and Q23 contributing between 5-7% of alleles. Recently, the ATXN2 CAG repeat has been identified as a target of adaptive selection in the CEU population. Mouse lines deficient for atxn2 develop marked hyperphagia and obesity raising the possibility that loss-of-function mutations in the ATXN2 gene may be related to energy balance in humans. Some linkage studies of obesity related phenotypes such as antipsychotic induced weight gain have reported significant lod scores on chromosome 12q24. We tested the hypothesis that rare loss-of-function ATXN2 variants cause obesity analogous to rare mutations in the leptin, leptin receptor and MC4R genes.
  
  
  RESULTS
  We sequenced the coding region of ATXN2 including intron-exon boundaries in 92 severely obese children with a body mass index (BMI) >3.2 standard deviations above age- and gender-adjusted means. We confirmed five previously identified single nucleotide polymorphisms (SNPs) and three new SNPs resulting in two synonymous substitutions and one intronic polymorphism. Alleles encoding >Q22 were overrepresented in our sample of obese children and contributed 15% of alleles in children identified by their parents as white. SNP rs695872 closely flanking the CAG repeat showed a greatly increased frequency of C/C homozygotes and G/C heterozygotes compared with reported frequencies in the CEU population.
  
  
  CONCLUSIONS
  Although we did not identify variants leading to novel amino acid substitutions, nonsense or frameshift mutations, this study warrants further examination of variation in the ATXN2 gene in obesity and related phenotypes in a larger case-control study with emphasis on rs695872 and CAG repeat structure.
authors.affiliation: Department of Neurology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Karla P
authors.initials: KP
authors.lastname: Figueroa
authors.forename: Sadaf
authors.initials: S
authors.lastname: Farooqi
authors.forename: Kristopher
authors.initials: K
authors.lastname: Harrup
authors.forename: Johnathan
authors.initials: J
authors.lastname: Frank
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pulst
mesh_terms: D017668:Age of Onset; D000818:Animals; D000067528:Ataxins; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009765:Obesity / Q000453:epidemiology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D000067528:Ataxins; D009419:Nerve Tissue Proteins