Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.
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.
Pitteloud
Nelly
N
Reproductive Endocrine Unit of the Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. npitteloud@partners.org
Quinton
Richard
R
Pearce
Simon
S
Raivio
Taneli
T
Acierno
James
J
Dwyer
Andrew
A
Plummer
Lacey
L
Hughes
Virginia
V
Seminara
Stephanie
S
Cheng
Yu-Zhu
YZ
Li
Wei-Ping
WP
Maccoll
Gavin
G
Eliseenkova
Anna V
AV
Olsen
Shaun K
SK
Ibrahimi
Omar A
OA
Hayes
Frances J
FJ
Boepple
Paul
P
Hall
Janet E
JE
Bouloux
Pierre
P
Mohammadi
Moosa
M
Crowley
William
W
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
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