CRHBP is highly conserved across vertebrates and in humans encodes a 322 amino acid protein that contains 5 disulphide bonds that are essential for CRH binding (Westphal and Seasholtz, 2006). The CRHBP SNPs that have been associated with stress-related phenotypes in our and other studies are located at the 3′ end of the gene. At the present time, no evidence has been provided that any of the SNPs in this region are or are not functional although Binder et al. (2010) did show that the variant allele of a 3′ SNP rs10473984 was associated with higher ACTH concentrations and speculated that this might be due to reduced CRHBP expression. It is noteworthy that a second CRHBP isoform has been identified in brain in which the terminal exon is spliced out in favor of two alternative exons that lie 3′ to the gene resulting in a truncation of the protein at the C-terminus with the normal 52 amino acids being replaced by 18 novel amino acids (Enoch et al., 2008). This change in peptide sequence might affect protein folding and stability that might alter CRH binding affinity.
