BES2005 Poster Presentations Growth and development (48 abstracts)
Two novel missense mutations in GPR54 in a subject with hypogonadotropic hypogonadism
RK Semple 1 , JC Achermann 2 , J Ellery 3 , IS Farooqi 1 , FE Karet 4 , RG Stanhope 5 , SP O'Rahilly 1 & SA Aparicio 3,6
1Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; 2Department of Medicine and Institute of Child Health, University College London, London, UK; 3Paradigm Therapeutics Ltd, Cambridge, UK; 4Department of Medical Genetics and Division of Renal Medicine, University of Cambridge, Cambridge, UK; 5Great Ormond Street Hospital for Children, London, UK; 6Department of Oncology, Hutchison-MRC Centre, University of Cambridge, Addenbrookes Hospital, Cambridge, 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 signalling assay in 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.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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