DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development.

Détails

ID Serval
serval:BIB_E34B12561F91
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development.
Périodique
Human molecular genetics
Auteur(s)
Bouilly J., Messina A., Papadakis G., Cassatella D., Xu C., Acierno J.S., Tata B., Sykiotis G., Santini S., Sidis Y., Elowe-Gruau E., Phan-Hug F., Hauschild M., Bouloux P.M., Quinton R., Lang-Muritano M., Favre L., Marino L., Giacobini P., Dwyer A.A., Niederländer N.J., Pitteloud N.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Statut éditorial
Publié
Date de publication
15/01/2018
Peer-reviewed
Oui
Volume
27
Numéro
2
Pages
359-372
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease characterized by absent puberty and infertility due to GnRH deficiency, and is often associated with anosmia [Kallmann syndrome (KS)]. The genetic etiology of CHH is heterogeneous, and more than 30 genes have been implicated in approximately 50% of patients with CHH. We hypothesized that genes encoding axon-guidance proteins containing fibronectin type-III (FN3) domains (similar to ANOS1, the first gene associated with KS), are mutated in CHH. We performed whole-exome sequencing in a cohort of 133 CHH probands to test this hypothesis, and identified rare sequence variants (RSVs) in genes encoding for the FN3-domain encoding protein deleted in colorectal cancer (DCC) and its ligand Netrin-1 (NTN1). In vitro studies of these RSVs revealed altered intracellular signaling associated with defects in cell morphology, and confirmed five heterozygous DCC mutations in 6 probands-5 of which presented as KS. Two KS probands carry heterozygous mutations in both DCC and NTN1 consistent with oligogenic inheritance. Further, we show that Netrin-1 promotes migration in immortalized GnRH neurons (GN11 cells). This study implicates DCC and NTN1 mutations in the pathophysiology of CHH consistent with the role of these two genes in the ontogeny of GnRH neurons in mice.
Mots-clé
Adult, Cohort Studies, DCC Receptor/genetics, DCC Receptor/metabolism, Female, Fibronectin Type III Domain, Gonadotropin-Releasing Hormone/deficiency, Humans, Hypogonadism/genetics, Hypogonadism/metabolism, Hypogonadism/pathology, Male, Mutation, Netrin-1/genetics, Netrin-1/metabolism, Neurons/metabolism, Neurons/pathology, Pedigree, Whole Exome Sequencing
Pubmed
Web of science
Open Access
Oui
Création de la notice
07/12/2017 19:22
Dernière modification de la notice
20/08/2019 16:07
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