RGD Reference Report - Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. - Rat Genome Database

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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.
RGD ID: 11567265
Pubmed: PMID:17235395   (View Abstract at PubMed)
PMCID: PMC1765517   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI29884   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hypogonadotropic hypogonadism 7 with or without anosmia  IAGP 11567265DNA:missense mutations:exon:p.L342S (c.1025T>C), p.R470L (c.1409G>T) (human)RGD 
hypogonadotropic hypogonadism 7 with or without anosmia  ISOFGFR1 (Homo sapiens)11567265; 11567265DNA:missense mutations:exon:p.L342S (c.1025T>C), p.R470L (c.1409G>T) (human)RGD 
hypogonadotropic hypogonadism 7 with or without anosmia  IAGP 11567265DNA:missense mutations: :p.Q106R and p.R262Q (human)RGD 
hypogonadotropic hypogonadism 7 with or without anosmia  ISOGNRHR (Homo sapiens)11567265; 11567265DNA:missense mutations: :p.Q106R and p.R262Q (human)RGD 
hypogonadotropic hypogonadism 7 with or without anosmia  IAGP 11567265DNA:deletion:intron:c.1159-14_-22del (human)RGD 
hypogonadotropic hypogonadism 7 with or without anosmia  ISONSMF (Homo sapiens)11567265; 11567265DNA:deletion:intron:c.1159-14_-22del (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Fgfr1  (Fibroblast growth factor receptor 1)
Gnrhr  (gonadotropin releasing hormone receptor)
Nsmf  (NMDA receptor synaptonuclear signaling and neuronal migration factor)

Genes (Mus musculus)
Fgfr1  (fibroblast growth factor receptor 1)
Gnrhr  (gonadotropin releasing hormone receptor)
Nsmf  (NMDA receptor synaptonuclear signaling and neuronal migration factor)

Genes (Homo sapiens)
FGFR1  (fibroblast growth factor receptor 1)
GNRHR  (gonadotropin releasing hormone receptor)
NSMF  (NMDA receptor synaptonuclear signaling and neuronal migration factor)


Additional Information