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- Title
Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism.
- Authors
Semple, R K; Achermann, J C; Ellery, J; Farooqi, I S; Karet, F E; Stanhope, R G; O'rahilly, S; Aparicio, S A
- 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.
- Subjects
AMINO acids; CELL receptors; COMPARATIVE studies; DOCUMENTATION; GENETIC polymorphisms; HYPOGONADISM; RESEARCH methodology; MEDICAL cooperation; GENETIC mutation; RESEARCH; RESEARCH funding; GENETIC testing; EVALUATION research; DISEASE prevalence
- Publication
Journal of Clinical Endocrinology & Metabolism, 2005, Vol 90, Issue 3, p1849
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2004-1418