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

Details

Serval ID
serval:BIB_E34B12561F91
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development.
Journal
Human molecular genetics
Author(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
Publication state
Published
Issued date
15/01/2018
Peer-reviewed
Oui
Volume
27
Number
2
Pages
359-372
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
Keywords
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
Yes
Create date
07/12/2017 20:22
Last modification date
20/08/2019 17:07
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