Idiopathic hypogonadotropic hypogonadism (IHH) consists of those patients without commonly anosmia (a poor sense of smell) or adrenal insufficiency. This subset of IHH results in reproductive failure that is caused by mutations of the GnRH (gonadotropin-releasing hormone) receptor (GNRHR) gene. Like all IHH patients, those affected experience delayed sexual development and low or apulsatile gona-dotropin levels. The impairment in sexual development, however, occurs in the absence of the anatomical abnormalities common to fertility disorders that affect the hypothalamic-pituitary axis (97,98).
The genetic defects for two of the more common X-linked subtypes of IHH, congenital IHH with anosmia (or Kallmann syndrome, KS), and IHH with adrenal insufficiency (adrenal hypoplasia congenita) are distinct from the forms of the disease caused by GnRH receptor (GnRHR) mutations. These forms of IHH are included for the sake of clarity.
The KS mutations were identified in the KAL gene and result in abnormal olfactory bulb development (99,100). The mutations responsible for the X-linked IHH with adrenal hypoplasia congenita were identified in the DAX1 gene. DAX1 encodes an orphan nuclear hormone receptor that regulates portions of reproductive development (101,102).
18.104.22.168 GnRHR Mutations that Result in Idiopathic IHH
Comparatively little is known about the molecular biology of the GnRHR mutations that result in idiopathic IHH. At least 15 mutations of the GnRHR have been described in IHH (98,103-105). Some of these mutations, such as Glu90Lys and Ser217Arg, have been found in vitro to be LOF mutations. Other GnRHR mutations, such as Asn10Lys, Thr32Ile, and Gln10Arg, have a somewhat reduced ability to elicit an inositol phosphate response in vitro (98).
Site-directed mutagenesis has been used to identify the significance of many GnRHR variants to receptor function. The Glu90Ala (106) and Arg139His (107) mutations were inactive in vitro, suggesting that these residues are probably critical to receptor activation. The 217Ser variant of TM 5, however, illustrates how the effect of an amino acid substitution can be context sensitive. Although the variant identified in patients, Ser217Arg, is completely inactive; a substitution of Ser217Gln and Ser217Tyr using site-directed mutagenesis results in a GnRHR with partial function. Therefore, some residues may not always be critical to receptor function as long as the substitution does not disrupt receptor structure because of the steric hindrance (98). In this manner, portions of the GnRHR that are involved in specific molecular functions have been isolated.
The advances made possible by isolating the GnRHR and its variants illustrate the potential applications of pharmacogenomics. The joining of clinical and structural biology has resulted in the identification of an antagonist that can selectively rescue most of the naturally occurring GnRHR mutants by increasing their cell surface expression (108). This is an example of a therapeutic strategy that would have been unimaginable before the pharmacogenomic paradigm of drug discovery.
This antagonist may act on GPCRs to stabilize misfolded proteins and prevent them from being targeted for degradation (97,98,109). The antagonist is permeant, named after its ability to recover the function of receptors before they are degraded or expressed incorrectly at the membrane. While still experimental, this example illustrates how an understanding of GPCR genomics and GPCR protein structure may facilitate the identification of drugs with novel mechanisms of action that may provide clinical intervention for complex developmental disorders.
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