title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Paediatric Endocrinology and Metabolism, Cukurova University, Faculty of Medicine, Adana, Turkey. ktopaloglu@cu.edu.tr
authors.forename: A Kemal
authors.initials: AK
authors.lastname: Topaloglu
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Lu
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Neslihan O
authors.initials: NO
authors.lastname: Mungan
authors.forename: Bilgin
authors.initials: B
authors.lastname: Yuksel
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Robert P
authors.initials: RP
authors.lastname: Millar
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011966:Receptors, LHRH / Q000235:genetics*; D014162:Transfection; D014421:Turkey
chemical_list: D011966:Receptors, LHRH