Introduction: INSL3 and its receptor LGR8, are essential for the first phase of testicular descent. Homozygous loss of either of the two genes in mice leads to cryptorchidism. Even though mutations in both homologous human genes are not a common cause of cryptorchidism. To date, only one missense mutation at codon 222 (T222P) of the LGR8 gene has been proposed as causative mutation for cryptorchidism. This conclusion was based on both functional in vitro studies and the lack of mutation in a large group of controls. The geographic origin of the mutation carriers suggested a founder effect in the Mediterranean area.
Objectives: We sought to define the frequency of the T222P mutation in four different countries in order to assess whether the screening for this mutation could be of use as a diagnostic genetic test.
Materials and methods: A total of 822 subjects (359 with a history of cryptorchidism and 463 controls) from Italy, Spain, Hungary and Egypt were genotyped for the T222P mutation by direct sequencing.
Results: The phenotypic expression of the mutation included also normal testicular descent. The mutation frequency was not significantly different in cryptorchid patients versus non cryptorchid controls (3.6 vs 1.7%). No significant geographic differences were observed in mutation frequencies. The haplotype analysis allowed to predict three distinct haplotypes i.e. three possible mutation events.
Conclusions: Our results suggest that the T222P mutation cannot be considered neither causative nor susceptibility factor for cryptorchidism. A true causative mutation in the LGR8 gene remains still to be identified.
03 - 07 May 2008
European Society of Endocrinology