title: A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor gene.
abstract: OBJECTIVE
  Mutations in the GnRH receptor (GnRH-R) gene cause hypogonadotrophic hypogonadism. Here, we present the molecular studies of the GnRH-R gene in three families with isolated hypogonadotrophic hypogonadism.
  
  
  METHODS
  Three unrelated families, with at least two members diagnosed with isolated hypogonadotrophic hypogonadism were included.
  
  
  METHODS
  DNA sequencing was performed after polymerase chain reaction amplification of each of the three exons of the gene.
  
  
  RESULTS
  A novel homozygous missense mutation, at nucleotide 268, turning glutamic acid into lysine, located at the second transmembrane domain of the GnRH-R gene was found in two patients pertaining to one of the families studied. Both parents and an unaffected brother were heterozygous carriers of one mutant allele, an unaffected sister was homozygote wild type. In the other two affected families no mutations were found in the GnRH-R gene.
  
  
  CONCLUSIONS
  This constitutes the first description of an spontaneous mutation located at the second transmembrane domain (Glu90Lys) of the GnRH-R, indicating that the integrity of glutamic acid at this position is crucial for receptor function. Also this report, complementing others, demonstrates that mutations are distributed throughout the GnRH-R gene and that as in the only other homozygous mutation previously described, affected patients present a complete form of hypogonadotrophic hypogonadism. Due to the fact that apparently consanguinity was present in our affected family, we presume that the mutation derived from a common ancestor, by a founder gene effect.
authors.affiliation: Research Unit in Developmental Biology, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México, D.F., México.
authors.forename: D
authors.initials: D
authors.lastname: Söderlund
authors.forename: P
authors.initials: P
authors.lastname: Canto
authors.forename: E
authors.initials: E
authors.lastname: de la Chesnaye
authors.forename: A
authors.initials: A
authors.lastname: Ulloa-Aguirre
authors.forename: J P
authors.initials: JP
authors.lastname: Méndez
mesh_terms: D000293:Adolescent; D000328:Adult; D003241:Consanguinity; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D018698:Glutamic Acid / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007006:Hypogonadism / Q000097:blood / Q000235:genetics*; D007986:Luteinizing Hormone / Q000097:blood; D008239:Lysine / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011966:Receptors, LHRH / Q000235:genetics*
chemical_list: D011966:Receptors, LHRH; D018698:Glutamic Acid; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D008239:Lysine