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Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism

Lookup NU author(s): Dr Richard Quinton, Professor Simon PearceORCiD

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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.


Publication metadata

Author(s): Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J, Dwyer A, Plummer L, Hughes V, Seminara S, Cheng Y-Z, Li W-P, Maccoll G, Eliseenkova AV, Olsen SK, Ibrahimi OA, Hayes FJ, Boepple P, Hall JE, Bouloux P, Mohammadi M, Crowley Jr W

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2007

Volume: 117

Issue: 2

Pages: 457-463

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation

URL: http://dx.doi.org/10.1172/JCI29884

DOI: 10.1172/JCI29884

PubMed id: 17235395


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Funding

Funder referenceFunder name
DE13686NIDCR NIH HHS
HD15788NICHD NIH HHS
HD028138NICHD NIH HHS
P50 HD028138NICHD NIH HHS
P30 HD028138NICHD NIH HHS
U54 HD028138NICHD NIH HHS
R01 DE013686NIDCR NIH HHS
R01 HD015788NICHD NIH HHS

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