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This version published online on December 14, 2004
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1418
A more recent version of this article appeared on March 1, 2005
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Submitted on July 25, 2004
Accepted on December 7, 2004

Two Novel Missense Mutations in GPR54 in a Patient with Hypogonadotropic Hypogonadism

R. K. Semple*, J. C. Achermann, J. Ellery, I. S. Farooqi, F. E. Karet, R. G. Stanhope, S. O'Rahilly, and S. A. Aparicio

Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K; Department of Medicine and Institute of Child Health, University College London, London, U.K; Paradigm Therapeutics Ltd, 214 Cambridge Science Park, Cambridge, U.K; University of Cambridge, Department of Oncology, Hutchison-MRC Centre, Addenbrookes CB2 2XZ; Great Ormond Street Hospital for Children, London, U.K; Department of Medical Genetics and Division of Renal Medicine, University of Cambridge, Cambridge, U.K.

* To whom correspondence should be addressed. E-mail: rks16{at}cam.ac.uk.

It has recently been shown that loss-of-function mutations of the G protein-coupled receptor GPR54 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 cells stably expressing GPR54, the C223R variant was found to exhibit profoundly impaired signaling, while 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.
Key words: GPR54 • KISS1 • kisspeptin • hypogonadotrophic hypogonadism




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