Molecular Defects Of The GnRH-Receptor Gene In Chinese Patients With Idiopathic Hypogonadotropic Hypogonadism And The Severity Of Hypogonadism

BackgroundGnRH plays an essential and central role in neuroendocrine control of reproductivefunction. The GnRH receptor is located on the plasma membrane of gonadotrophs, pituitarycells that synthesize the gonadotrophins LH and FSH. This receptor belongs to thesuperfamily of G protein-coupled receptors, and is preferentially coupled to the Gq/11protein; its activation by GnRH analogues stimulates the synthesis and release of LH andFSH. Human mutations in the gonadotropin-releasing hormone receptor (GnRHR) genecause normosmic idiopathic hypogonadotropic hypogonadism (IHH). At least19differentmutations have been identified in this G-protein-coupled receptor, which consist mostly ofmissense mutations.ObjectivesTo identify and determine the frequency of mutations in the coding region of thegonadotropin-releasing hormone receptor (GnRHR) gene in forty Chinese patients withnormosmic idiopathic hypogonadotropic hypogonadism (IHH) and establishgenotype/phenotype correlations where possible.MethodsThe diagnosis of HH was based on absent or incomplete sexual development after17yr. of age in girls and18yr. in boys (as puberty should be completed by16in girls and17in boys and if it doesn’t that could be hypogonadism) associated with low or normal levelsof LH in both sexes and low levels of testosterone in males and of estradiol in females. Allpatients presented with a normal sense of smell in olfactory specific test.40IHH patientsand40controls were screened for mutations in the coding sequence of GnRHR gene. Thecoding region of the GnRHR gene was amplified by PCR and directly sequenced.ResultsA missense mutation serine168arginine (S168R) located in the fourth transmembranedomain of the GnRHR gene was identified in a homozygous state in one male withcomplete HH, the S168R mutation has been previously shown to cause complete loss ofreceptor function because hormone binding to the receptor is completely impaired. In another patient, a compound heterozygous mutation (Gln106Arg and Arg262Gln) wasidentified in a male with partial HH, the Gln106Arg mutation located in the firstextracellular loop of GnRH-R, this mutation decrease but not eliminate GnRH binding,while Arg262Gln mutation located in the third extracellular loop of GnRHR and onlydecreases signal transduction. A good correlation between genotype and phenotype wasfound in our patients. The patient, who is homozygous for the completely inactivatingS168R mutation, has complete HH. In addition, the affected patient who is compoundheterozygotes for the Gln106Arg-Arg262Gln mutations, has partial HH.Conclusions1GnRHR mutations can be classified into partial or complete loss of function mutations.2Partially inactivating substitutions of the GnRHR frequently found in familialhypogonadotrophic hypogonadism are Q106R and R262Q.3Comparison of compound heterozygous with homozygous patients suggests that theirphenotype and the response to GnRH are determined by the GnRHR variant with theless severe loss of function.