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Two Novel Missense Mutations in G Protein-Coupled Receptor 54 in a Patient with Hypogonadotropic Hypogonadism

Department of Clinical Biochemistry (R.K.S., I.S.F., S.O.) and Department of Medical Genetics and Division of Renal Medicine (F.E.K.), Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Department of Medicine and Institute of Child Health (J.C.A.), University College London, London WC1N 1EH, United Kingdom; Paradigm Therapeutics Ltd. (J.E., S.A.A.), Cambridge CB4 0WA, United Kingdom; Department of Oncology (S.A.A.), Hutchison Medical Research Council Centre, University of Cambridge, Addenbrookes CB2 2XZ, United Kingdom; and Great Ormond Street Hospital for Children (R.G.S.), London WC1N 3JH, United Kingdom

Address all correspondence and requests for reprints to: Robert Semple, Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge CB2 2QR, United Kingdom. E-mail: rks16{at}cam.ac.uk.

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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