FUNCTIONAL AND CLINICAL CONSEQUENCES OF MUTATIONS IN THE FSH RECEPTOR

The follicle-stimulating hormone (FSH) is essential for normal gametog enesis. In females FSH is required for ovarian development and follicl e maturation whereas in males FSH determines Sertoli cell number and q uantitatively and qualitatively normal spermatogenesis. FSH action is mediated by a G-protein coupled receptor expressed solely in granulosa and Sertoli cells. The FSH-receptor (FSHR) gene is localized on chrom osome 2 p21 and spans a region of 54 kb. It consists of ten exons; exo n one to nine encode the large extracellular domain and the transmembr ane domain is comprised of exon ten. Mutations in the FSHR gene could severely affect gametogenesis and result in infertility. Therefore scr eening programs have been initiated, in which patients with disturbed fertility were searched for mutations in the FSHR gene. Several Finnis h families were identified displaying an inherited pattern of ovarian dysgenesis, a disease leading to streaky underdeveloped ovaries and pr imary amenorrhea. By genetic linkage the locus of the genetic defect w as confined to chromosome 2 p21. Analysis of the FSHR gene resulted in the identification of a mutation (Ala189Val) homozygous in all affect ed females. Functional studies revealed that the mutation affects the proper protein folding and thereby inactivates the receptor. In a male patient hypophysectomized because of a pituitary tumor, who despite u ndetectable serum gonadotropins had normal semen parameters, we hypoth esized an activating mutation of the FSHR. Screening of exon ten of th e FSHR gene resulted in the identification of a Asp567Gly transition i n the third intracytoplasmatic loop. Functional studies resulted in a 1.5-fold increase in basal cAMP production compared to wild type FSHR, indicating that the heterozygous mutation leads to a ligand-independe nt constitutive activation of the FSHR. This patient provides an excep tional model of nature defining the role of FSH in human spermatogenes is. Mutations of the FSHR might have differential effects in each gend er. For example activating mutations have not been described in women, therefore it is not clear whether the constitutive activity of the re ceptor could disturb normal follicular development resulting in certai n infertility. Copyright (C) 1996 Elsevier Science Ireland Ltd.