Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.

Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. Research Abstract Details 

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Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. Abstract Text:

Nelly Pitteloud,Richard Quinton,Simon Pearce,Taneli Raivio,James Acierno,Andrew Dwyer,Lacey Plummer,Virginia Hughes,Stephanie Seminara,Yu-Zhu Cheng,Wei-Ping Li,Gavin Maccoll,Anna V Eliseenkova,Shaun K Olsen,Omar A Ibrahimi,Frances J Hayes,Paul Boepple,Janet E Hall,Pierre Bouloux,Moosa Mohammadi,William Crowley,

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.

Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. Publishing Authors By Initials

N Pitteloud,R Quinton,S Pearce,T Raivio,J Acierno,A Dwyer,L Plummer,V Hughes,S Seminara,YZ Cheng,WP Li,G Maccoll,AV Eliseenkova,SK Olsen,OA Ibrahimi,FJ Hayes,P Boepple,JE Hall,P Bouloux,M Mohammadi,W Crowley,

For similar proteins: transcription factors research abstracts see: proteins: transcription factors research

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Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: The Journal of clinical investigation

VOLUME: 117

Page Numbers: 457-63

Journal Abbreviation: J. Clin. Invest.

ISSN: 0021-9738

DAY: 18

MONTH: 01

YEAR: 2007

Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7802877

Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. Keywords Mesh Terms:

KEYWORDS: Transcription Factors

MESH TERMS: genetics

Chemical & Substance for Abstract: Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. Information

Substance Name: Receptor, Fibroblast Growth Factor, Type

Registry Number: EC 2.7.1.112

Grant and Affiliation Information for Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.

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

Country: United States

AGENCY: United States NICHD

GRANT: HD15788

ACRONYM: HD

MEDLINETA: J Clin Invest

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