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

  • Bouilly J Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Messina A Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Papadakis G Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Cassatella D Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Xu C Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Acierno JS Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Tata B UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, University of Lille, 59000 Lille, France.
  • Sykiotis G Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Santini S Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Sidis Y Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Elowe-Gruau E Division of Endocrinology, Diabetology and Obesity, Department of Pediatrics, Centre Hospitalier Universitaire Vaudois Lausanne, 1005 Lausanne, Switzerland.
  • Phan-Hug F Division of Endocrinology, Diabetology and Obesity, Department of Pediatrics, Centre Hospitalier Universitaire Vaudois Lausanne, 1005 Lausanne, Switzerland.
  • Hauschild M Division of Endocrinology, Diabetology and Obesity, Department of Pediatrics, Centre Hospitalier Universitaire Vaudois Lausanne, 1005 Lausanne, Switzerland.
  • Bouloux PM Center for Neuroendocrinology, Royal Free Campus, University College Medical School, London WC1E6BT, UK.
  • Quinton R Institute of Genetic Medicine and the Royal Victoria Infirmary, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne NE13BZ, UK.
  • Lang-Muritano M Department of Endocrinology/Diabetology and Children's Research Centre, University Children's Hospital Zurich, 8091 Zurich, Switzerland.
  • Favre L Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Marino L Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Giacobini P UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, University of Lille, 59000 Lille, France.
  • Dwyer AA Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Niederländer NJ Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • Pitteloud N Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
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  • 2017-12-05
Published in:
  • Human molecular genetics. - 2018
Adult
Cohort Studies
DCC Receptor
Female
Fibronectin Type III Domain
Gonadotropin-Releasing Hormone
Humans
Hypogonadism
Male
Mutation
Netrin-1
Neurons
Pedigree
Whole Exome Sequencing
English 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.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/47424
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