Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.

نویسندگان

  • Nelly Pitteloud
  • Richard Quinton
  • Simon Pearce
  • Taneli Raivio
  • James Acierno
  • Andrew Dwyer
  • Lacey Plummer
  • Virginia Hughes
  • Stephanie Seminara
  • Yu-Zhu Cheng
  • Wei-Ping Li
  • Gavin Maccoll
  • Anna V Eliseenkova
  • Shaun K Olsen
  • Omar A Ibrahimi
  • Frances J Hayes
  • Paul Boepple
  • Janet E Hall
  • Pierre Bouloux
  • Moosa Mohammadi
  • William Crowley
چکیده

Idiopathic hypogonadotropic hypogonadism (IHH) due to defects of gonadotropin-releasing hormone (GnRH) secretion and/or action is a developmental disorder of sexual maturation. To date, several single-gene defects have been implicated in the pathogenesis of IHH. However, significant inter- and intrafamilial variability and apparent incomplete penetrance in familial cases of IHH are difficult to reconcile with the model of a single-gene defect. We therefore hypothesized that mutations at different IHH loci interact in some families to modify their phenotypes. To address this issue, we studied 2 families, one with Kallmann syndrome (IHH and anosmia) and another with normosmic IHH, in which a single-gene defect had been identified: a heterozygous FGF receptor 1 (FGFR1) mutation in pedigree 1 and a compound heterozygous gonadotropin-releasing hormone receptor (GNRHR) mutation in pedigree 2, both of which varied markedly in expressivity within and across families. Further candidate gene screening revealed a second heterozygous deletion in the nasal embryonic LHRH factor (NELF) gene in pedigree 1 and an additional heterozygous FGFR1 mutation in pedigree 2 that accounted for the considerable phenotypic variability. Therefore, 2 different gene defects can synergize to produce a more severe phenotype in IHH families than either alone. This genetic model could account for some phenotypic heterogeneity seen in GnRH deficiency.

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Hypogonadotropic Hypogonadism due to Novel FGFR1 Mutations

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عنوان ژورنال:
  • The Journal of clinical investigation

دوره 117 2  شماره 

صفحات  -

تاریخ انتشار 2007