Semple, RK; Achermann, JC; Ellery, J; Farooqi, IS; Karet, FE; Stanhope, RG; O'Rahilly, S; Semple, RK; Achermann, JC; Ellery, J; Farooqi, IS; Karet, FE; Stanhope, RG; O'Rahilly, S; Aparicio, SA; - view fewer (2005) Two novel missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. The Journal of Clinical Endocrinology & Metabolism , 90 (3) 1849 - 1855. 10.1210/jc.2004-1418.

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Abstract

It has recently been shown that loss-of-function mutations of the G protein-coupled receptor (GPR) 54 lead to isolated hypogonadotropic hypogonadism (IHH) in mice and humans. Such mutations are thought to be rare, even within the clinical IHH population, and only a handful of alleles have been described, making further screening of IHH populations imperative. We examined the genes encoding GPR54 and its putative endogenous ligand, kisspeptin-1, for mutations in a cohort of 30 patients with normosmic HH or delayed puberty. One subject with HH, of mixed Turkish-Cypriot and Afro-Caribbean ancestry, was found to be a compound heterozygote for two previously undescribed missense mutations in GPR54: cysteine 223 to arginine (C223R) in the fifth transmembrane helix and arginine 297 to leucine (R297L) in the third extracellular loop. Assessed in vitro using a previously described sensitive signaling assay in cells stably expressing GPR54, the C223R variant was found to exhibit profoundly impaired signaling, whereas the R297L variant showed a mild reduction in ligand-stimulated activity across the ligand dose range. These novel mutations provide further evidence that human HH may be caused by loss-of-function mutations in GPR54.

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