Male mice deficient in insulin-like 3 hormone (Insl3) or its receptor, Great/Lgr8, exhibit cryptorchidism. Recently, sequence analysis of the human INSL3 and GREAT genes identified several allelic variants. These include polymorphisms without apparent functional consequence and a few alleles encoding products with compromised function. However, loss-of-function alleles appear to be rare in human cryptorchidism. Most patients studied to date are presumed to have had sporadic cryptorchidism. We postulated that any genotypic variants predisposing to cryptorchidism would be more prevalent among patients with familial cryptorchidism. 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. We directly sequenced all 20 amplicons and compared them with the wild-type alleles. We detected two silent substitutions and one missense (A60T) substitution in exon 1 of INSL3 and two silent substitutions in exon 12 and one missense (I604V) substitution in exon 17 of GREAT, all previously described. We found that in vitro the I604V GREAT variant receptor responds to INSL3 stimulation similarly to the wild-type receptor. We found polymorphic alleles of INSL3 and GREAT, but no deleterious mutations among individuals with familial cryptorchidism. Thus, mutations in these two genes are responsible only for a small proportion of familial cryptorchidism.
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