Bouilly, J;
Messina, A;
Papadakis, G;
Cassatella, D;
Xu, C;
Acierno, JS;
Tata, B;
... Pitteloud, N; + view all
(2018)
DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development.
Human Molecular Genetics
, 27
(2)
pp. 359-372.
10.1093/hmg/ddx408.
Preview |
Text
Bouloux_DCC NTN1 complex mutations.pdf - Accepted Version Download (874kB) | Preview |
Preview |
Text
Bouloux_DCC NTN1 complex mutations Supplementary information.pdf - Accepted Version Download (1MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/hmg/ddx408 |
| Publisher version: | http://dx.doi.org/10.1093/hmg/ddx408 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Genetics & Heredity, NETRIN-1 RECEPTOR DCC, KALLMANN-SYNDROME, AXON GUIDANCE, MIRROR MOVEMENTS, MIGRATORY PATHWAY, SEQUENCE VARIANTS, HORMONE NEURONS, CELL-MIGRATION, BRAIN, GENE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10054799 |
Archive Staff Only
 |
View Item |
