title: A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism.
abstract: BACKGROUND
  Loss-of-function mutations of the kisspeptin-1 receptor gene, KISS1R, have been identified in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH).
  
  
  OBJECTIVE
  To investigate KISS1R defects in patients with absent or delayed puberty.
  
  
  METHODS
  We investigated KISS1R gene defects in a cohort of 99 Brazilian patients with nIHH or constitutional delay of puberty (CDP).
  
  
  METHODS
  The entire coding region of KISS1R was amplified by PCR followed by automatic sequencing. In addition, screening for KISS1R exonic deletions was performed by multiplex ligation-dependent probe amplification.
  
  
  RESULTS
  One novel homozygous KISS1R mutation was identified in two siblings with nIHH. This variant was an insertion/deletion (indel) mutation characterized by the deletion of three nucleotides (GCA) at position -2 to -4, and by the insertion of seven nucleotides (ACCGGCT) at the same position, within the 3' splice acceptor site of intron 2 of KISS1R. The brothers who carried this KISS1R mutation had no clinical evidence of pubertal development at the ages of 14 and 20 years. Computational analysis of this indel mutation predicted the generation of an abnormal protein. In addition, a new heterozygous KISS1R variant (p.E252Q) was identified in a male patient with sporadic nIHH. However, in vitro studies of this variant did not demonstrate functional impairment. Only known polymorphisms were identified in patients with CDP.
  
  
  CONCLUSIONS
  Loss-of-function mutations of KISS1R represents a rare cause of nIHH, and was absent in patients with CDP. We have described a novel KISS1R homozygous splice acceptor site mutation in the familial form of nIHH.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42 da Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, 05403-900 São Paulo, Brazil.
authors.forename: M G
authors.initials: MG
authors.lastname: Teles
authors.forename: E B
authors.initials: EB
authors.lastname: Trarbach
authors.forename: S D
authors.initials: SD
authors.lastname: Noel
authors.forename: G
authors.initials: G
authors.lastname: Guerra-Junior
authors.forename: A
authors.initials: A
authors.lastname: Jorge
authors.forename: D
authors.initials: D
authors.lastname: Beneduzzi
authors.forename: S D
authors.initials: SD
authors.lastname: Bianco
authors.forename: A
authors.initials: A
authors.lastname: Mukherjee
authors.forename: M T
authors.initials: MT
authors.lastname: Baptista
authors.forename: E M
authors.initials: EM
authors.lastname: Costa
authors.forename: M
authors.initials: M
authors.lastname: De Castro
authors.forename: B B
authors.initials: BB
authors.lastname: Mendonça
authors.forename: U B
authors.initials: UB
authors.lastname: Kaiser
authors.forename: A C
authors.initials: AC
authors.lastname: Latronico
mesh_terms: D000818:Animals; D001938:Brazil; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D006720:Homozygote; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D011628:Puberty, Delayed / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D000074502:Receptors, Kisspeptin-1; D035781:Siblings
chemical_list: C118688:KISS1R protein, human; D022821:RNA Splice Sites; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1