Of marsupials and men: “Backdoor” dihydrotestosterone synthesis in male sexual differentiation

► Marsupials have an alternative 'backdoor' pathway leading from 17OHP to dihydrotestosterone. ► It has been unknown if humans possess this pathway or the key enzymes involved. ► Two families with 46,XY DSD had mutations in AKR1C2, a 3αHSD enzyme unique to this pathway. ► The mutant enzymes had decreased activity in vitro. ► These studies establish that human male sex differentiation employs both classical and backdoor pathways.