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- Title
Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.
- Authors
Pitteloud, Nelly; Quinton, Richard; Pearce, Simon; Raivio, Taneli; Acierno, James; Dwyer, Andrew; Plummer, Lacey; Hughes, Virginia; Seminara, Stephanie; Cheng, Yu-Zhu; Li, Wei-Ping; Maccoll, Gavin; Eliseenkova, Anna V; Olsen, Shaun K; Ibrahimi, Omar A; Hayes, Frances J; Boepple, Paul; Hall, Janet E; Bouloux, Pierre; Mohammadi, Moosa; Crowley, William
- Abstract
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.
- Publication
The Journal of clinical investigation, 2007, Vol 117, Issue 2, p457
- ISSN
0021-9738
- Publication type
Journal Article
- DOI
10.1172/JCI29884