Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: Identification and characterization of two discrete FSH receptor isoforms

In a search for pathophysiological causes of idiopathic male infertility we investigated the occurrence of mutations of the FSH receptor in 48 men wit h this disorder. The entire FSH receptor gene was analyzed by single strand ed conformation polymorphism analysis (SSCP). A heterozygous point mutation without functional consequences, exchanging Val to Ala in codon 341, was f ound in one patient. SSCP analysis led to the identification of 2 polymorph isms in exon 10 associated in 2 discrete FSH receptor allelic variants, i.e . Thr(307)-Asn(680) and Ala(307)-Ser(680). The frequency and distribution o f the two allelic variants was further analyzed in 86 proven fathers and 75 infertile men by SSCP (codon 307) and restriction fragment length polymorp hism (codon 680). The 2 receptor isoforms showed similar Mendelian distribu tion in proven fathers and in infertile men. Serum FSH, inhibin B, and comb ined testicular volume did not differ between subjects with different recep tor isoforms. Binding studies in transiently transfected COS-7 cells showed similar binding affinity for the two receptor variants. Moreover, the Ala( 307)-Ser(680) and the Thr(307)-Asn(680) FSH receptors responded in vitro to FSH with comparable cAMP production. These data suggest that different iso forms of the FSH receptor with similar functional properties exist in norma l and infertile men. We conclude that mutations of the FSH receptor or the FSH receptor genotype do not play a pathogenic role in male idiopathic infe rtility. The possibility that different FSH isoforms might interact differe ntly with the 2 receptor variants remains to be investigated.