Molecular genetic, biochemical, and clinical implications of gonadotropin receptor mutations

Human reproductive function is regulated mainly by luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Mutations of the human LH/ chorionic gonadotropin receptor (LHR) and the FSH receptor (FSHR) leading to either constitutive activation or inactivation of the receptors have been identified. All activating mutations of the LHR and the FSHR are located within the exon encoding the transmembrane domain while the inactivating mutations are scattered throughout the coding sequence. A number of activating and inactivating mutations of the LHR have been found while only one activating and three inactivating mutations of the FSHR are known. Activating mutations of the LHR cause familial male-limited precocious puberty (FMPP) while that of the FSHR has been shown to restore the reproductive capability of a hypophysectomized male. Inactivating mutations of the LHR cause Leydig cell hypoplasia (LCH) in males while that of the FSHR causes hereditary hypergonadotropic ovarian dysgenesis (ODG) in females. Activating mutations of both receptors are dominant while inactivating mutations are recessive. Genotype-phenotype correlation is best established for the inactivating mutations of LHR. Severity of clinical phenotype in LCH correlates with the amount of residual activity of the mutated LHR. Comparison of the clinical impact of the activating and the inactivating mutations of the receptors indicates that male reproductive capacity depends primarily on LH while female reproductive capacity depends primarily on FSH.