Targeted inactivation of the insulin-like hormone 3 (insl3) gene in male mice results in altered gubernacular development, disrupted testis decent, and cryptorchidism.
These findings demonstrate that INSL3-LGR8/GREAT mutations are frequently associated with human cryptorchidism, and that the only clinical consequence of alterations of the INSL3-LGR8/GREAT system seems to be failure of the testis to descend normally in the scrotum during embryonic development, without affecting the spermatogenic and endocrine components of the testis itself.
We isolated genomic DNA from 13 individuals with personal and family histories of cryptorchidism and used polymerase chain reaction to amplify all exons of both INSL3 and GREAT, as well as INSL3 proximal promoter sequence, including a putative SF-1 transcription factor binding site.
Because earlier studies indicated that mutation of the INSL3 gene is not associated with the development of human cryptorchidism, this study analysed whether mutations in the LGR8 gene could be associated with this disorder.
This finding agrees with the rare occurrence of INSL3 gene mutations in human cryptorchidism, but needs to be confirmed in a larger series of selected patients.
Although to date no mutations have been found in the human INSL3 gene responsible for cryptorchidism, one causative mutation in the INSL3 receptor (LGR8 or GREAT) has been reported.
Our results indicate that mutations in the RLF gene are not a common reason for cryptorchidism and that the common G178A polymorphism has no apparent relationship with this condition.
While both the insulin-like peptide 3 (INSL3) and its receptor, relaxin family peptide receptor 2 (RXFP2), have been demonstrated to control testicular descent in mice, their link to human cryptorchidism is weak, with no clear cause-effect demonstrated.
To study the consequences of an aberrant testicular environment in cryptorchidism we used a mouse model with a deletion of Rxfp2 gene resulting in a high intra-abdominal testicular position.