title: A novel severe N-terminal splice site KISS1R gene mutation causes hypogonadotropic hypogonadism but enables a normal development of neonatal external genitalia.
abstract: BACKGROUND
  Kisspeptin 1 receptor (KISS1R) gene mutations are rare but have recently become an important etiology of normosmic isolated hypogonadotropic hypogonadism (IHH).
  
  
  OBJECTIVE
  To characterize the genetic defect, the phenotype, and response to therapy of three IHH siblings with a novel severe KISS1R mutation.
  
  
  METHODS
  Three siblings (16- and 22-year-old sisters and their 20-year-old brother) born to consanguineous parents with normal neonatal external genitalia presented with no pubertal development, normosmia, and a low response to GNRH stimulation. Homozygosity mapping, KISS1R gene sequencing, and RNA expression were performed.
  
  
  RESULTS
  The females' basal low estradiol level (50 pmol/l) failed to rise in response to human chorionic gonadotropin (hCG). The brother's low testosterone (1.87 nmol/l) responded to combined hCG and human menopausal gonadotropin (hCG) and HMG therapies, but the testes remained small (1-2 ml). Secondary sexual characteristics were attained by exogenous sex steroid replacement. SNP array studies revealed shared homozygosity for a chromosome 19 region encompassing KISS1R. Sequencing revealed a novel homozygous KISS1R mutation at the nt-1 canonical acceptor splice site of intron 1 in affected siblings. The mother (menarche at 14 years) was heterozygous. cDNA sequencing showed that the G>A mutation results in skipping of exon 2 and a premature stop codon at residue 151.
  
  
  CONCLUSIONS
  The novel severe N-terminal KISS1R splice site (c.245-1G>A) mutation results in IHH. Heterozygous female carriers may manifest a subtle fertile phenotype. The subnormal gonadal response to hCG in patients may implicate a direct role of KISS1R in gonadal function. The normal neonatal virilization in a male homozygous to this severe mutation challenges the hypothesis that KISS1R is required for fetal development of male external genitalia.
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, Hadassah Hebrew University Medical Center, Mount Scopus, PO Box 24035, Jerusalem 91240, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Breuer
authors.forename: Maha
authors.initials: M
authors.lastname: Abdulhadi-Atwan
authors.forename: Sharon
authors.initials: S
authors.lastname: Zeligson
authors.forename: Hila
authors.initials: H
authors.lastname: Fridman
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
authors.forename: David H
authors.initials: DH
authors.lastname: Zangen
mesh_terms: D000293:Adolescent; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D005835:Genitalia / Q000254:growth & development*; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000503:physiopathology; D007231:Infant, Newborn / Q000254:growth & development; D008297:Male; D020125:Mutation, Missense / Q000502:physiology; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D000074502:Receptors, Kisspeptin-1; D012720:Severity of Illness Index; D035781:Siblings; D055815:Young Adult
chemical_list: C118688:KISS1R protein, human; D022821:RNA Splice Sites; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1