Molecular Genetics of the Follitropin Receptor: Structural Diversity, Mutations, Gene Knock Out and Biological Implications

Pituitary follitropin (follicle stimulating hormone, FSH) an important member of the glycoprotein hormone family that is essential for reproduction functions by binding to a receptor(s) localized on discrete ovarian and testicular cells. The pre mRNA of the mammalian large single gene of >250kb (as deduced in the human genome) undergoes extensive alternative splicing creating proteins of different structural motifs. The mechanisms and relationships of four ovine follitropin receptor (FSH-R) variants that we have studied are highlighted in this article as example. These include the following – the classical Gs coupled receptor, a dominant negative form, a single transmembrane domain growth factor type I receptor and a potentially soluble form. As their signaling properties are different, it is proposed that receptor diversity exists to integrate hormone signaling mechanisms to coordinate developmental and steroidogenic functions of gonads. Several mutations of the follitropin receptor in humans observed in different parts of the world are known to compromise reproductive efficiency to varying degrees. Completely inactivating mutations are not common as the affected individual (particularly women) is rendered sterile. These conclusions are fully supported by studies in our receptor knockout mouse model (the FORKO mouse) in which we have deleted the entire FSH-R repertoire. The null females are sterile while the mutant males have reduced fertility. Mutant females as well as aging heterozygous females with estrogen deficiency and hormonal imbalances duplicate many conditions that exist in postmenopausal women. This model has provided unexpected experimental paradigms to investigate a variety of health issues related to quality of life during menopause. Thus, the null mutant and particularly the heterozygous female dubbed the “Menopause Mouse” exhibit osteoporosis, obesity, ovarian and uterine tumors, as well as changes in the brain regions associated with memory. Phenotypes in the +/mice are age dependent. Mutant males also show distinct phenotypes with aberrant sperm and are also helpful in understanding the mechanisms that affect sperm production and quality. We propose that comparison of normal and mutant gonads and other steroid dependent target tissues will lead to the identification of downstream gene (products) involved in specific steps of their development and function. It is anticipated that the mutants might also be helpful in elucidating mechanisms related to ovarian and uterine pathogenesis.