Gonadotropin receptor mutations are also quite rare. There are both activating and inactivating mutations in these genes, with widely varying phenotypic effects. Activating receptor mutations can be classified into four categories: (1) receptor activation in the absence of ligand hormone; (2) increased sensitivity of the receptor to its normal ligand; (3) relaxed specificity of the receptor to ligands; and (4) acquired novel functions of the mutated receptor. All activating gonadotropin receptor mutations detected have been missense point mutations that are localized to the transmembrane region or its vicinity (see Figs. 2 and 3). These mutations produce a structural alteration, activating constitu-tively the signal transduction machinery of the transmembrane region. Most clearly, receptor activation without ligand explains the altered function of these mutations. Abnormal phenotypes occur in heterozygous individuals because activation of the translation product of a single allele is sufficient to initiate the altered functional response.
Several mechanisms can also underlie receptor inactivation: (1) decreased synthesis of receptor protein; (2) aberrant intracellular processing; (3) reduced or absent ligand-binding activity; (4) impaired or absent signal transduction; (5) inability to anchor to the plasma membrane; (6) inability to dimerize, if needed, for signal transduction; or (7) increased degradation. Unlike the activating mutations, the types of inactivating mutations vary from point nonsense and missense mutations to various size insertions and deletions. In this case, only homozygotes or compound heterozygotes for two different inactivating mutations produce a clear phenotype because the normal function of a single receptor allele supplies a sufficient number of functional receptors to sustain normal gonadotropin action.
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