title: Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism.
abstract: OBJECTIVE
  To determine the frequency of mutations of the gonadotropin-releasing hormone receptor (GnRHR) and of the G protein-coupled receptor 54 (GPR54) genes in normosmic idiopathic hypogonadotropic hypogonadism (IHH).
  
  
  METHODS
  In a retrospective study we analyzed the GnRHR and the GPR54 genes of 45 IHH patients and 50 controls. Genomic DNA was amplified by PCR to obtain partially overlapping amplicons encompassing the exon-intron boundaries of the GnRHR and GPR54 genes and analyzed by single-stranded conformation polymorphism gel electrophoresis and/or DNA sequencing.
  
  
  RESULTS
  One heterozygous R262Q mutation of the GnRHR gene was identified in one patient with familial IHH. The silent single-nucleotide polymorphism (SNP) 453C > T occurred at the same frequency in patients and controls. One patient with sporadic IHH and consanguineous parents showed a novel homozygous sequence variation of the GPR54 gene (1001_1002insC) resulting in an open reading frame shift and elongation of 43 amino acids with an increased number of proline residues in the intracellular receptor domain. This patient had delayed puberty, low testosterone (3.4 nmol/l), and low-normal LH and FSH levels responsive to GnRH. Pulsatile GnRH administration normalized testosterone levels and induced spermatogenesis sufficiently to induce a pregnancy with assisted reproduction. Two common SNPs in exon 1 and exon 5 of the GPR54 gene showed similar frequency distribution and hormonal profiles in IHH and controls.
  
  
  CONCLUSIONS
  Mutations of the GnRHR and of the GPR54 gene are rare in IHH and should be investigated especially in cases with autosomal recessive transmission. Common SNPs of the GnRHR and GPR54 genes do not play any role in IHH.
authors.affiliation: Institute of Reproductive Medicine of the University, D-48129 Münster, Germany.
authors.forename: Fabio
authors.initials: F
authors.lastname: Lanfranco
authors.forename: Jörg
authors.initials: J
authors.lastname: Gromoll
authors.forename: Sigrid
authors.initials: S
authors.lastname: von Eckardstein
authors.forename: Eva M
authors.initials: EM
authors.lastname: Herding
authors.forename: Eberhard
authors.initials: E
authors.lastname: Nieschlag
authors.forename: Manuela
authors.initials: M
authors.lastname: Simoni
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D003241:Consanguinity; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D044088:Receptors, Galanin / Q000235:genetics*; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH / Q000235:genetics*
chemical_list: C118688:KISS1R protein, human; D043562:Receptors, G-Protein-Coupled; D044088:Receptors, Galanin; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH; D020962:Heterotrimeric GTP-Binding Proteins