title: Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.
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.
authors.affiliation: Reproductive Endocrine Unit of the Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. npitteloud@partners.org
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.forename: Richard
authors.initials: R
authors.lastname: Quinton
authors.forename: Simon
authors.initials: S
authors.lastname: Pearce
authors.forename: Taneli
authors.initials: T
authors.lastname: Raivio
authors.forename: James
authors.initials: J
authors.lastname: Acierno
authors.forename: Andrew
authors.initials: A
authors.lastname: Dwyer
authors.forename: Lacey
authors.initials: L
authors.lastname: Plummer
authors.forename: Virginia
authors.initials: V
authors.lastname: Hughes
authors.forename: Stephanie
authors.initials: S
authors.lastname: Seminara
authors.forename: Yu-Zhu
authors.initials: YZ
authors.lastname: Cheng
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Li
authors.forename: Gavin
authors.initials: G
authors.lastname: Maccoll
authors.forename: Anna V
authors.initials: AV
authors.lastname: Eliseenkova
authors.forename: Shaun K
authors.initials: SK
authors.lastname: Olsen
authors.forename: Omar A
authors.initials: OA
authors.lastname: Ibrahimi
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Hayes
authors.forename: Paul
authors.initials: P
authors.lastname: Boepple
authors.forename: Janet E
authors.initials: JE
authors.lastname: Hall
authors.forename: Pierre
authors.initials: P
authors.lastname: Bouloux
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.forename: William
authors.initials: W
authors.lastname: Crowley
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D017124:Conserved Sequence; D004247:DNA / Q000235:genetics; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D005838:Genotype; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency; D006579:Heterozygote; D006801:Humans; D007006:Hypogonadism / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D017436:Kallmann Syndrome / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011966:Receptors, LHRH / Q000235:genetics; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics
chemical_list: C496456:FGF8 protein, human; C484844:GNRHR protein, human; C411985:NSMF protein, human; D011966:Receptors, LHRH; D014157:Transcription Factors; D051524:Fibroblast Growth Factor 8; D007987:Gonadotropin-Releasing Hormone; D004247:DNA; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1