Article: article from journal or magazin.
Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.
Journal of Clinical Investigation
Publication types: Case Reports, pdf: Research Article
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.
Adult, Amino Acid Sequence, Base Sequence, Conserved Sequence, DNA/genetics, Female, Fibroblast Growth Factor 8/metabolism, Genotype, Gonadotropin-Releasing Hormone/deficiency, Heterozygote, Humans, Hypogonadism/etiology, Hypogonadism/genetics, Kallmann Syndrome/genetics, Male, Models, Genetic, Models, Molecular, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Receptor, Fibroblast Growth Factor, Type 1/chemistry, Receptor, Fibroblast Growth Factor, Type 1/genetics, Receptors, LHRH/genetics, Sequence Deletion, Sequence Homology, Amino Acid, Transcription Factors/genetics
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