Insulin-like 3/relaxin-like factor gene mutations are associated with cryptorchidism

Cryptorchidism is a common anomaly of male sexual differentiation. Two phas es of testicular descent are recognized, transabdominal and inguinoscrotal. With evidence that androgens and Mullerian inhibitory hormone were not com pletely responsible for testicular descent, the existence of a third testic ular hormone mediating testicular descent was postulated. Insulin-like 3 (I NSL3) [also known as relaxin-like factor (RLF) and Leydig insulin-like prot ein (LEY I-L)] is a member of the insulin/relaxin hormone superfamily that is highly expressed in Leydig cells. The phenotype of transgenic mice with targeted deletion of the Insl3 gene was bilateral cryptorchidism with morph ological evidence of abnormal gubernacular development. With this implicit evidence that Insl3 mediates testicular descent in mice, we performed mutat ion detection analysis of the coding regions of the 2 exon INSL3 gene in ge nomic DNA samples obtained from 145 formerly cryptorchid patients and 36 ad ult male controls. Single-strand conformational polymorphism analysis was u sed for the mutation detection studies. Two mutations, R49X and P69L, and s everal polymorphisms were identified. Both mutations were located in the co nnecting peptide region of the protein. The frequency of INSL3/RLF gene mut ations as a cause of cryptorchidism is low, because only 2 of 145 (1.4%) fo rmerly cryptorchid patients were found to have mutations.