2. Academic Validation
  3. Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism

Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism

  • Am J Hum Genet. 2020 Jan 2;106(1):58-70. doi: 10.1016/j.ajhg.2019.12.003.
Andrea Messina 1,  Kristiina Pulli 2,  Sara Santini 1,  James Acierno 3,  Johanna Känsäkoski 4,  Daniele Cassatella 3,  Cheng Xu 1,  Filippo Casoni 5,  Samuel A Malone 6,  Gaetan Ternier 6,  Daniele Conte 7,  Yisrael Sidis 1,  Johanna Tommiska 4,  Kirsi Vaaralahti 2,  Andrew Dwyer 1,  Yoav Gothilf 8,  Giorgio R Merlo 7,  Federico Santoni 1,  Nicolas J Niederländer 1,  Paolo Giacobini 6,  Taneli Raivio 9,  Nelly Pitteloud 10
Affiliations

Affiliations

  • 1 Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, 1011 Lausanne, Switzerland.
  • 2 Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.
  • 3 Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, 1011 Lausanne, Switzerland; Università Vita-Salute San Raffaele, Via Olgettina 58, 20132, Milan, Italy.
  • 4 Department of Physiology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.
  • 5 Inserm, Jean-Pierre Aubert Research Center, Development and Plasticity of the Neuroendocrine Brain, Unité 1172 Lille, 59045 Lille, France; Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy, Milan 20132, Italy; Università Vita-Salute San Raffaele, Via Olgettina 58, 20132, Milan, Italy.
  • 6 Inserm, Jean-Pierre Aubert Research Center, Development and Plasticity of the Neuroendocrine Brain, Unité 1172 Lille, 59045 Lille, France.
  • 7 Department of Molecular Biotechnology and Health Science, University of Torino, 10126 Torino, Italy.
  • 8 Department of Neurobiology, George S. Wise Faculty of Life Sciences and Sagol School of Neurosciences, University of Tel Aviv, Tel Aviv 69978, Israel.
  • 9 Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; Pediatric Research Center, New Children's Hospital, Helsinki University Hospital, 00290 Helsinki, Finland.
  • 10 Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, 1011 Lausanne, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland. Electronic address: nelly.pitteloud@chuv.ch.
PMID: 31883645 DOI: 10.1016/j.ajhg.2019.12.003
Abstract

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by infertility and the absence of puberty. Defects in GnRH neuron migration or altered GnRH secretion and/or action lead to a severe gonadotropin-releasing hormone (GnRH) deficiency. Given the close developmental association of GnRH neurons with the olfactory primary axons, CHH is often associated with anosmia or hyposmia, in which case it is defined as Kallmann syndrome (KS). The genetics of CHH are heterogeneous, and >40 genes are involved either alone or in combination. Several CHH-related genes controlling GnRH ontogeny encode proteins containing fibronectin-3 (FN3) domains, which are important for brain and neural development. Therefore, we hypothesized that defects in other FN3-superfamily genes would underlie CHH. Next-generation Sequencing was performed for 240 CHH unrelated probands and filtered for rare, protein-truncating variants (PTVs) in FN3-superfamily genes. Compared to gnomAD controls the CHH cohort was statistically enriched for PTVs in neuron-derived neurotrophic factor (NDNF) (p = 1.40 × 10-6). Three heterozygous PTVs (p.Lys62∗, p.Tyr128Thrfs∗55, and p.Trp469∗, all absent from the gnomAD database) and an additional heterozygous missense mutation (p.Thr201Ser) were found in four KS probands. Notably, NDNF is expressed along the GnRH neuron migratory route in both mouse embryos and human fetuses and enhances GnRH neuron migration. Further, knock down of the zebrafish ortholog of NDNF resulted in altered GnRH migration. Finally, mice lacking Ndnf showed delayed GnRH neuron migration and altered olfactory axonal projections to the olfactory bulb; both results are consistent with a role of NDNF in GnRH neuron development. Altogether, our results highlight NDNF as a gene involved in the GnRH neuron migration implicated in KS.

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