Abstract
BackgroundExpansion 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.Methodology/Principal FindingsWe 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/SignificanceAlthough 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.
Highlights
The ataxin-2 protein is a 1312 amino acid protein of unknown function encoded by 25 coding exons of the spinocerebellar ataxia type 2 (SCA2)/ATXN2 gene [1,2]
We sequenced the 25 coding exons of the human ATXN2 gene in 92 severely obese children enrolled in the Genetics of Obesity Study (GOOS) with a mean body mass index .3.2 standard deviations above the mean
The ATXN2 gene was initially identified as the gene mutated in SCA2, a human neurodegenerative disease
Summary
The ataxin-2 protein is a 1312 amino acid protein of unknown function encoded by 25 coding exons of the SCA2/ATXN2 gene [1,2]. The protein contains a polyglutamine domain, which is encoded by a CAG/CAA repeat in exon 1 of the gene. Expansion of the CAG repeat and the consequent elongation of the polyQ domain to $32 repeats causes the neurodegenerative disease spinocerebellar ataxia type 2 (SCA2). The region containing the ATXN2 gene on 12q24.1 has undergone significant selection in Central Europeans (CEU) [5]. 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. 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
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