title: Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism.
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.
authors.affiliation: Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 2QR, United Kingdom. rks16@cam.ac.uk
authors.forename: R K
authors.initials: RK
authors.lastname: Semple
authors.forename: J C
authors.initials: JC
authors.lastname: Achermann
authors.forename: J
authors.initials: J
authors.lastname: Ellery
authors.forename: I S
authors.initials: IS
authors.lastname: Farooqi
authors.forename: F E
authors.initials: FE
authors.lastname: Karet
authors.forename: R G
authors.initials: RG
authors.lastname: Stanhope
authors.forename: S
authors.initials: S
authors.lastname: O'rahilly
authors.forename: S A
authors.initials: SA
authors.lastname: Aparicio
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007006:Hypogonadism / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018013:Receptors, Neuropeptide / Q000235:genetics*
chemical_list: C118688:KISS1R protein, human; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018013:Receptors, Neuropeptide