Mutation Ala(171)Thr stabilizes the gonadotropin-releasing hormone receptor in its inactive conformation, causing familial hypogonadotropic hypogonadism.

Mutations of the GnRH receptor have been recognized as a cause of familial gonadotropin deficiency. We here identify and functionally characterize a novel human GnRH receptor variant bearing an Ala171Thr substitution located at transmembrane helix 4 (TMH4). The affected kindred displays severe hypogonadotropic hypogonadism. After in vitro expression in human embryonic kidney 293T cells, the Ala171Thr mutant GnRH receptor exhibited a lack of phospholipase C activity in signal transduction. Specific receptor binding of 125I-labeled GnRH ligand was undetectable in Ala171Thr GnRH receptor-transfected cells. Molecular modeling and dynamic simulation of the Ala171Thr GnRH receptor suggests the introduction of a stable hydrogen bond between residue Thr171 and Tyr119 side-chains at a distance of 2 A. Although spatially distant from the GnRH ligand-binding site, this hydrogen bond impedes conformational mobility of the TMH3 and TMH4 domains required for sequential ligand binding and receptor activation, thus stabi...