The unraveling of the structure of the human genome has allowed for major advances in the diagnostics of inherited diseases. Besides clear disease-causing mutations, the emerging knowledge about single nucleotide and microsatellite polymorphisms in the human genome is adding a new level of complexity to genomic function, providing the structural basis for individual variability of the genome and its pheno-typic expression. All mutations can, in principle, be classified as inactivating, activating, or neutral, i.e., with no effect on function of the encoded protein. The hormone ligand mutations that are known today are almost invariably inactivating. The polymorphisms, by definition, are neutral, or they have only minor effects at the functional level. In some cases, they may even offer a functional advantage to their carriers. In the case of hormone receptors, the inactivating mutations block receptor function through a variety of mechanisms, whereas with activating mutations, the receptor becomes con-stitutively activated in the absence of hormone, or it acquires novel functions not present in the wild-type (WT) receptor.

Reproductive functions, like all functions on the human body that are under genetic control, are affected by specific mutations and polymorphisms of key genes. The focus

From: Male Hypogonadism: Basic, Clinical, and Therapeutic Principles Edited by: S. J. Winters © Humana Press Inc., Totowa, NJ

of this chapter is to review the currently known mutations in the three gonadotropins, the pituitary luteinizing hormone (LH), its placental analog, human chorionic gonadotropin (hCG), and the pituitary follicle-stimulating hormone (FSH), as well as their cognate receptors (R), the LH-R and FSH-R. Specific forms of male gonadal dysfunction are caused by these mutations. Common polymorphisms exist in the gonadotropins and their receptor genes, and they may be responsible for borderline alterations of gonadal function. This review emphasizes the role of gonadotropin and gonadotropin receptor mutations in male gonadal dysfunction. The polymorphisms of these genes with phenotypic effects are also described, as well as the relevant genetically-modified animal models when they enhance the molecular pathogenesis of the mutations.

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