Chunk #28 — REGULATORY ELEMENTS IN THE UNTRANSLATED REGIONS — Genetic variants at the 3′UTR — 3′UTR length and alteration of the polyadenylation signal
Several genes contain multiple polyadenylation sites which, by changing the length of the 3′ untranslated regions, may alter the number of binding sites for miRNAs and RBPs, thus modifying protein expression patterns and influencing disease. An example is represented by a point mutation in the canonical poly-A signal (AAUAAA→AAUGAA) of the forkhead box P3 gene (FOXP3), highly expressed in regulatory T cells. The mutation reduces the protein expression and causes a rare autoimmune disease, named immune dysfunctions polyendocrinopathy enteropathy X-linked, also known as IPEX syndrome.53 Similarly, mutations in the poly-A signal of α- and β-globin genes cause a decreased production of the corresponding proteins resulting in thalassemia.54–56 Conversely, the introduction of a novel alternative poly-A signal can dysregulate the protein production, leading to increased risk for disease. An example is represented by the recently discovered variant, associated to both multiple sclerosis and systemic lupus erythemathosus, which will be described below.17
