  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.
