A genetic basis for functional hypothalamic amenorrhea.

Détails

Ressource 1Télécharger: BIB_C988869DDA2B.P001.pdf (806.09 [Ko])
Etat: Public
Version: Author's accepted manuscript
Document(s) secondaire(s)
Télécharger: 5_21247312.pdf (1479.57 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_C988869DDA2B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
A genetic basis for functional hypothalamic amenorrhea.
Périodique
New England Journal of Medicine
Auteur(s)
Caronia L.M., Martin C., Welt C.K., Sykiotis G.P., Quinton R., Thambundit A., Avbelj M., Dhruvakumar S., Plummer L., Hughes V.A., Seminara S.B., Boepple P.A., Sidis Y., Crowley W.F., Martin K.A., Hall J.E., Pitteloud N.
ISSN
1533-4406[electronic], 0028-4793[linking]
Statut éditorial
Publié
Date de publication
2011
Peer-reviewed
Oui
Volume
364
Numéro
3
Pages
215-225
Langue
anglais
Résumé
Background: Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea.
Methods: We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations.
Results: Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q.
Conclusions: Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.)
Mots-clé
Amenorrhea/etiology, Amenorrhea/genetics, Extracellular Matrix Proteins/genetics, Female, Gene Expression, Genetic Predisposition to Disease, Gonadotropin-Releasing Hormone/deficiency, Gonadotropin-Releasing Hormone/genetics, Humans, Hypogonadism/genetics, Hypothalamic Diseases/complications, Hypothalamic Diseases/genetics, Luteinizing Hormone/secretion, Mutation, Nerve Tissue Proteins/genetics, Protein Precursors/genetics, Receptor, Fibroblast Growth Factor, Type 1/genetics, Receptors, G-Protein-Coupled/genetics, Receptors, LHRH/genetics, Receptors, Peptide/genetics, Sequence Analysis, DNA
Pubmed
Web of science
Open Access
Oui
Création de la notice
04/02/2011 16:42
Dernière modification de la notice
20/08/2019 16:44
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