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R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.

Authors: Maione, L  Albarel, F  Bouchard, P  Gallant, M  Flanagan, CA  Bobe, R  Cohen-Tannoudji, J  Pivonello, R  Colao, A  Brue, T  Millar, RP  Lombes, M  Young, J  Guiochon-Mantel, A  Bouligand, J 
Citation: Maione L, etal., PLoS One. 2013 Jul 25;8(7):e69616. doi: 10.1371/journal.pone.0069616. Print 2013.
Pubmed: (View Article at PubMed) PMID:23936060
DOI: Full-text: DOI:10.1371/journal.pone.0069616

Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence. This mutation was identified in a CpG islet in nine nCHH subjects from four unrelated families, giving evidence for a putative "hot spot". Interestingly, all the nCHH patients carry this mutation in heterozygosis that strikingly contrasts with the recessive inheritance associated with frame shift and non-sense mutations. Therefore, after exclusion of a second genetic event, a comprehensive functional characterization of the mutant R31C GnRH was undertaken. Using different cellular models, we clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind GnRH-receptor, to activate MAPK pathway and to trigger inositol phosphate accumulation and intracellular calcium mobilization. In addition it is less able than wild type to induce lh-beta transcription and LH secretion in gonadotrope cells. Finally, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo patho-physiology of this form of nCHH.

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RGD Object Information
RGD ID: 9685133
Created: 2014-12-17
Species: All species
Last Modified: 2014-12-17
Status: ACTIVE



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