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Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.

Authors: Pitteloud, N  Quinton, R  Pearce, S  Raivio, T  Acierno, J  Dwyer, A  Plummer, L  Hughes, V  Seminara, S  Cheng, YZ  Li, WP  Maccoll, G  Eliseenkova, AV  Olsen, SK  Ibrahimi, OA  Hayes, FJ  Boepple, P  Hall, JE  Bouloux, P  Mohammadi, M  Crowley, W 
Citation: Pitteloud N, etal., J Clin Invest. 2007 Feb;117(2):457-63. Epub 2007 Jan 18.
Pubmed: (View Article at PubMed) PMID:17235395
DOI: Full-text: DOI:10.1172/JCI29884

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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RGD Object Information
RGD ID: 11567265
Created: 2016-12-05
Species: All species
Last Modified: 2016-12-05
Status: ACTIVE



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