Evolution of the Primate Androgen Receptor: A Structural Basis for Disease

Abstract.

Androgen effects mediated by the androgen receptor (AR) are essential for male reproductive development and virilization. Comparison of AR DNA coding sequence from five primate species, Homo sapiens (human), Pan troglodytes (chimpanzee), Papio hamadryas (baboon), Macaca fascicularis (macaque), and Eulemur fulvus collaris (collared brown lemur), supports their phylogeny with complete conservation of the DNA and steroid binding domain protein sequence. A linear increase in trinucleotide repeat expansion of homologous CAG and GGC sequences occurs in the NH₂-terminal transcriptional activation region and is proportional to the time of species divergence. A serine phosphate/glutamine repeat interaction is observed where increasing CAG repeat length is associated with an increased rate of serine 94 phosphorylation. Disparity in the calculated and apparent molecular weight with CAG repeat expansion of an AR NH₂-terminal fragment suggests self-aggregation with increasing glutamine repeat length into the pathological range. These results suggest that a CAG/glutamine repeat expanded during divergence of the higher primate species, which may have a direct effect on AR structure and support a common pathway in CAG trigenic diseases in the pathophysiology of neurodegeneration observed in X-linked spinal bulbar and muscular atrophy.