A Family with Hypogonadotropic Hypogonadism and Mutations in the Gonadotropin-Releasing Hormone Receptor

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Abstract
Hypogonadotropic hypogonadism is often associated with anosmia in a condition known as Kallmann's syndrome. The gene for the X-linked form of Kallmann's syndrome has been mapped to chromosome Xp22.3,1 and several mutations have been described.2-4 In idiopathic hypogonadotropic hypogonadism there is no anosmia, and the involved genes have not been characterized. One possible candidate is the gene for gonadotropin-releasing hormone (GnRH), especially since hypogonadal mice with the deletion of this gene have been identified.5 However, no abnormality of the gene for GnRH has been found in several patients with idiopathic hypogonadotropic hypogonadism.6-9 The gene for the GnRH receptor is another candidate in this disease. This gene was recently cloned, and its product proved to be a G-protein–coupled receptor with seven transmembrane segments and an extracellular amino terminus but no intracellular carboxy terminus.10-13 Activation of this receptor results in increased activity of phospholipase C and mobilization of intracellular calcium by means of the Gq/G11 group of G proteins.14 The gene comprises three exons15 and maps to the long arm of chromosome 4.15,16