• PMID: 15598687
• Gene Name: GPR54
• Condition: Hypogonadotropic hypogonadism
• Association: 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 activit
• Mutation: C223R, R297L
• Population size: 30
• Population details: 30 patients with normosmic HH or delayed puberty
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Hypogonadotropic hypogonadism

Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism

Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, O'rahilly S, Aparicio SA.

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. FAU - Semple, R K AU - Semple RK AD - Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 2QR, United Kingdom. rks16@cam.ac.uk FAU - Achermann, J C AU - Achermann JC FAU - Ellery, J AU - Ellery J FAU - Farooqi, I S AU - Farooqi IS FAU - Karet, F E AU - Karet FE FAU - Stanhope, R G AU - Stanhope RG FAU - O'rahilly, S AU - O'rahilly S