INSL3/LGR8 role in testicular descent and cryptorchidism

Cryptorchidism, generally referred to a failure of testicular descent into the scrotum, is the most frequent (up to 3-4% at birth) congenital anomaly in newborn boys. Cryptorchidism is closely associated with impaired fertility, and represents an established risk factor for testicular cancer. Like other genital defects, cryptorchidism is believed to be caused by either endocrine or genetic abnormalities, or both. Recent elucidation of the molecular mechanism of the rodent testicular descent, and, in particular, the critical role of Insl3 (insulin-like 3) and its receptor Great/Lgr8 encouraged the search for naturally occurring mutations in the human homologues of these genes in the affected patient population. Genetic analysis revealed several functionally deleterious mutations in both INSL3 and GREAT/LGR8 genes. However, although some of mutations were found only in cryptorchid patients, it remains to be verified whether there is a causative link between the presence of mutations in INSL3 or GREAT/LGR8 and the undescended testis phenotype in men. The data and analysis of published studies indicate that mutations in these two genes might account for only a small portion of all cases of this disease in the human population.