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      Molecular Genetic Analysis of Normosmic Hypogonadotropic Hypogonadism in a Turkish Population: Identification and Detailed Functional Characterization of a Novel Mutation in the Gonadotropin-Releasing Hormone Receptor Gene

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          Background/Aims: Currently known mutations account for less than 15% of cases with normosmic hypogonadotropic hypogonadism (nIHH). The objective of the study was to identify novel hereditary associations in the pathogenesis of nIHH. Methods: We investigated 26 Turkish patients with nIHH (21 males and 5 females) from 22 families. The coding regions of the GnRH receptor, GnRH1, GPR54, and KISS1 genes were directly sequenced. Results: In two sisters, a novel homozygous missense mutation, R139C, located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GnRH receptor was identified. The R139C mutation almost completely abolished plasma membrane expression while having little effect on GnRH-binding affinity. The mutant receptor expression was rescued by a membrane-permeant, non-peptide GnRH receptor antagonist IN3. Conclusions: Consistent with the previous studies we were able to find mutations in only 7.6% of a well-defined group of patients with nIHH, which further suggests that yet unidentified genetic associations to explain nIHH exist.

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          A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor.

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

            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.
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              Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency


                Author and article information

                S. Karger AG
                March 2007
                28 March 2007
                : 84
                : 5
                : 301-308
                aDivision of Paediatric Endocrinology and Metabolism, Cukurova University, Faculty of Medicine, Adana, Turkey; bMedical Research Council Human Reproductive Sciences Unit, Queen’s Medical Research Institute, Edinburgh, and cDepartments of Medicine and Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
                98147 Neuroendocrinology 2006;84:301–308
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 4, References: 28, Pages: 8
                GnRH, Gonadotropins, Gonadal Steroids and Reproduction


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