A. GR polymorphisms and acquired mutations. Exons within the GR precursor mRNA are denoted with a rectangle and shading indicates that the NTD is encoded by exon 2, the DBD is encoded by exons 3 and 4, and the C-terminal region is encoded by exons 5-9. The proximal and distal regions of exon 9 are denoted α and β, respectively. Introns are marked with hashed bars. The arrows in the top panel indicate polymorphisms that do not result in amino acid changes, whereas the arrows in the bottom panel indicate polymorphisms that do result in amino acid changes. Furthermore, the locations of the L753F and Δ702 GR mutations that are associated with acquired glucocorticoid resistance to therapy in vivo are shown in the bottom panel. B. The GR splice variants. GRβ mRNA is produced from splicing of exon 8 to exon 9β, and the resulting protein contains 15 unique amino acids at the C-terminus (amino acids 728-742). GRγ mRNA is generated by alternative usage of a splice donor site at the exon 3 / exon 4 boundary and encodes for a protein containing an arginine insertion (R453) between the two zinc fingers of the DBD. The GR-A variant is produced from splicing of exon 4 to exon 8. Therefore, exons 5 – 7 are deleted. GR-P is formed by a failure to splice exon 7 to exon 8. Thus, GR-P contains the splice donor site of exon 7 followed by intact intronic sequences. Due to the deletion of 3’ exons, GR-A and GR-P lack significant portions of the LBD.

A. Steroid hormone receptors contain three major functional regions, the N-terminal transactivation domain (NTD), the central DNA-binding domain (DBD), and the C-terminal ligand-binding domain (LBD). The region located between the DBD and LBD is known as the hinge region (H). The DBD and LBD are highly conserved among receptors, and percentages indicate amino acid identity between these domains when compared to the respective domains within GRα. The numbers correspond to amino acid positions, asterisks represent internal N-terminal methionine residues conserved between the human, rat, and mouse. B. Domain organization of the GRα translational isoforms. Alternative initiation of translation gives rise to the GRα translational isoforms GRα-A, GRα-B, GRα-C1, GRα-C2, GRα-C3, GRα-D1, GRα-D2, and GRα-D3. The horizontal lines indicate functional regions embedded within the GRα protein. Due to deletions within the N-terminus, the translational isoforms lack portions of the NTD.