Novel Evolution of the Mineralocorticoid Receptor in Humans compared to Chimpanzees, Gorillas and Orangutans

Abstract

Five distinct full-length mineralocorticoid receptor (MR) genes have been identified in humans. These human MRs can be distinguished by the presence or absence of an in-frame insertion of 12 base pairs coding for Lys, Cys, Ser, Trp (KCSW) in their DNA-binding domain (DBD) and the presence of two amino acid mutations in their amino terminal domain (NTD). Two human MRs with the KCSW insertion (MR-KCSW) and three human MRs without KCSW in the DBD have been identified. The three human MRs without KCSW contain either (Ile-180, Ala-241) or (Val-180, Val-241) or (Ile-180, Val-241) in their NTD. The two human MRs with KCSW contain either (Val-180, Val-241) or (Ile-180, Val-241) in their NTD. Human MR-KCSW with (Ile-180, Ala-241) has not been cloned. In contrast, chimpanzees contain two MRs with KCSW and two MRs without KCSW in their DBD and both contain only Ile180, Val-241 in their NTDs. Each pair of chimpanzee MRs differ at another amino acid in the NTD. A chimpanzee MR with either Val-180, Val-241 or Ile-180, Ala-241 in the NTD has not been cloned. Gorillas and orangutans each contain one MR with KCSW in the DBD and one MR without KCSW. Both gorilla and orangutan MRs contain I-180, Val-241 in their NTD. Neither Val-180, Val-241 nor Ile-180,Ala-241 are found in the NTD in either a gorilla MR or an orangutan MR. These data suggest that human MRs with Val-180, Val-241 or Ile-180, Ala-241 in the NTD evolved after humans and chimpanzees diverged from their common ancestor. These unique human MRs may have had a role in the divergent evolution of humans from chimpanzees. Studies are underway to characterize transcriptional activation of the five human MRs by aldosterone, cortisol, and other corticosteroids for comparison with each other to elucidate the roles of these MRs in human physiology.

Lysine-Cysteine-Serine-Tryptophan Inserted into the DNA-Binding Domain of Human Mineralocorticoid Receptor Increases Transcriptional Activation by Aldosterone

“…The human MR cloned by Arriza et al [1] has 984 amino acids (MR984a), and this is the MR that has been widely studied [7,[9][10][11]13,15,24]. However, our BLAST search of GenBank [41] revealed that MR984a is not the only human MR in GenBank (Figure 2). GenBank also in their NTD may have been important in the evolution of humans from chimpanzees [41].…”

“…However, our BLAST search of GenBank [41] revealed that MR984a is not the only human MR in GenBank (Figure 2). GenBank also in their NTD may have been important in the evolution of humans from chimpanzees [41].…”

“…We propose that MRs with (Ile-180, Ala-241) or (Val-180, Val-241) in their NTD evolved in humans after divergence from chimpanzees and the evolution of these MRs. In the light of the diverse physiological functions of the MR in humans in regulating transcription in kidney, brain, heart, skin, lungs and other tissues [11,13–22], the evolution of human MRs with (Ile-180, Ala-241) or (Val-180, Val-241) in their NTD may have been important in the evolution of humans from chimpanzees [41].…”

“…Thus, humans were found to contain two almost identical MR transcripts, in which their DBDs differ by only four amino acids. The number of distinct human MR genes expanded after a BLAST analysis of GenBank with the human MR sequence identified differences at codons 180 and 241 in the NTD of MR-984 and MR-988 in humans [41] (Figure 2). Human MR-984a, cloned by Arriza et al [1], has been studied for transcriptional activation by aldosterone and other corticosteroids [1,26,27,29,30].…”

Lysine-Cysteine-Serine-Tryptophan Inserted into the DNA-Binding Domain of Human Mineralocorticoid Receptor Increases Transcriptional Activation by Aldosterone

“…Thus, humans were found to contain two almost identical MR transcripts, in which their DBDs differ by only four amino acids. The number of distinct human MR genes expanded after a BLAST analysis of GenBank with the human MR sequence identi ed differences at codons 180 and 241 in the NTD of MR-984 and MR-988 in humans [41] (Fig. 2).…”