Another example is represented by the PPP1R3 gene, encoding the muscle-specific glycogen-targeting regulatory PP1 subunit, which is involved in the regulation of glycogen synthesis in skeletal muscle. Xia and colleagues identified a polymorphism (ARE) in the 3′UTR of the PPP1R3 gene, which reduces the distance between two mRNA-destabilizing sequence ATTTA. The polymorphism is characterized by a 10-nucleotide (allele ARE1) versus a 2-nucleotide interval (allele ARE2). Interestingly, ARE2 was associated with insulin resistance, increased prevalence of type 2 diabetes and reduced expression of this PPP1R3 subunit, causing a reduction in the half-life of the corresponding mRNA. Three proteins of 43, 80, and 139 kDa seem to bind the polymorphic ARE region and the less stable ARE2 allele shows higher protein binding, suggesting the role of the ARE2 in reducing mRNA stability.75
