Loss of function mutations of the GnRH receptor: A new cause of hypogonadotropic hypogonadism

The association of hypogonadotropic hypogonadism with anosmia defines Kallm ann's syndrome. The gene of the X-linked form of this syndrome has been clo ned and several mutations described. However, the relatively small number o f hypogonadotropic hypogonadic patients with Kallmann's gene defects suppor ts the hypothesis that other genes may be involved, Idiopathic hypogonadotr opic hypogonadism (IHH) is not associated with anosmia, The GnRH gene was e xcluded asa candidate gene in IHH since no abnormality was found in several patients, The action of the GnRH is mediated through a G-protein coupled r eceptor present in the cell membrane of gonadotropes, The GnRH receptor was thus another candidate gene, Recently, we described the first patient with partial hypogonadotropic hypogonadism without anosmia caused by loss of fu nction mutations of the GnRH receptor. We compare this first family with a new family presenting complete hypogonadotropic hypogonadism and a variable degree of gonadotrope deficiency in the affected kindred, and discuss geno type-phenotype correlation.