R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.
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.
Université Paris-Sud, Faculté de Médecine Paris-Sud Unité mixte de Recherche en Santé 693, Le Kremlin Bicetre, France.
Luigi
L
Maione
Frederique
F
Albarel
Philippe
P
Bouchard
Megan
M
Gallant
Colleen A
CA
Flanagan
Regis
R
Bobe
Joelle
J
Cohen-Tannoudji
Rosario
R
Pivonello
Annamaria
A
Colao
Thierry
T
Brue
Robert P
RP
Millar
Marc
M
Lombes
Jacques
J
Young
Anne
A
Guiochon-Mantel
Jerome
J
Bouligand
D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018899:CpG Islands; D005260:Female; D005786:Gene Expression Regulation; D052681:Gonadotrophs / Q000378:metabolism / Q000473:pathology; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007006:Hypogonadism / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D007295:Inositol Phosphates / Q000378:metabolism; D037101:Luteinizing Hormone, beta Subunit / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D011966:Receptors, LHRH / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D007295:Inositol Phosphates; D037101:Luteinizing Hormone, beta Subunit; D011498:Protein Precursors; D011966:Receptors, LHRH; C050866:progonadoliberin I; D007987:Gonadotropin-Releasing Hormone; D002118:Calcium