Minimum CAG repeat in the human calmodulin-1 gene 5' untranslated region is required for full expression

The human calmodulin-1 gene (hCALM1) contains a (CAG)7 repeat in its 5'-untranslated region (5'-UTR). We found this repeat to be stable and nonpolymorphic in the human population. To determine whether the repeat region affects hCALM1 expression and whether repeat expansions to numbers known to be associated with disease in other genes may alter expression, we tested luciferase reporter genes driven by the hCALM1 promoter and 5'-UTR containing 0, 7 (wild-type), 20, and 45 CAG repeats in human NT2/D1 teratoma cells. Interestingly, the repeat deletion, (CAG)0, decreased expression by 45%, while repeat expansions to (CAG)20 and (CAG)45, or the insertion of a scrambled (C,A,G)7 sequence did not alter gene expression. These data indicate (1) that the endogenous repeat element is required for full expression of hCALM1, and (2) that some triplet repeat expansions in the 5'-UTR of protein-coding genes may be well tolerated and even optimize gene expression.