Short CAG repeat variation as a regulatory factor in health and disease

Short cytosine-adenine-guanine (CAG) trinucleotide repeats, which encode polyglutamine (polyQ) tracts, are prevalent features of genes enriched in transcriptional and regulatory functions, including the androgen receptor (AR) and huntingtin (HTT). While expanded CAG repeats are well established in neurodegenerative disease pathogenesis, the functional significance of short, non-pathogenic repeat lengths remains underappreciated. This review connects evidence demonstrating that short CAG/polyQ tracts act as dynamic modulators of protein conformation, transcriptional activity, and protein-protein interactions. Variation within physiological repeat ranges influences receptor sensitivity, cellular signaling, and phenotypic diversity. The AR serves as a central model, where shorter repeat lengths enhance transactivation and androgen responsiveness and are associated with increased prostate cancer risk, while longer non-expanded repeats are linked to reduced receptor activity and modest reproductive and metabolic effects. Mechanistically, repeat length and sequence composition jointly influence repeat stability, RNA structure, and downstream regulatory processes. Beyond AR, short CAG variation contributes to neuropsychiatric phenotypes and broader regulatory networks. Collectively, short CAG repeats function as quantitative regulators of gene activity, shaping disease susceptibility, physiological variation, and evolutionary adaptation.