Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism
| Autor: | Andrew A. Dwyer, Cheng Xu, Federico Santoni, Samuel A. Malone, Gaetan Ternier, Nicolas J Niederländer, Taneli Raivio, Sara Santini, Daniele Conte, Johanna Tommiska, Filippo Casoni, Kristiina Pulli, Daniele Cassatella, Andrea Messina, Nelly Pitteloud, Johanna Känsäkoski, Giorgio R. Merlo, Yoav Gothilf, Kirsi Vaaralahti, Yisrael Sidis, James S. Acierno, Paolo Giacobini |
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| Přispěvatelé: | Messina, Andrea, Pulli, Kristiina, Santini, Sara, Acierno, Jame, Känsäkoski, Johanna, Cassatella, Daniele, Xu, Cheng, Casoni, Filippo, Malone, Samuel A., Ternier, Gaetan, Conte, Daniele, Sidis, Yisrael, Tommiska, Johanna, Vaaralahti, Kirsi, Dwyer, Andrew, Gothilf, Yoav, Merlo, Giorgio R., Santoni, Federico, Niederländer, Nicolas J., Giacobini, Paolo, Raivio, Taneli, Pitteloud, Nelly, STEMM - Stem Cells and Metabolism Research Program, Raivio Group, Research Programs Unit, Faculty of Medicine, University of Helsinki, Department of Physiology, University Management, Medicum, HUS Children and Adolescents, Children's Hospital |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Kallmann syndrome PROTEIN Cohort Studies Mice 0302 clinical medicine Neurotrophic factors Cell Movement Missense mutation Genetics (clinical) Zebrafish GnRH Neuron Mice Knockout Neurons 1184 Genetics developmental biology physiology Pedigree INSIGHTS medicine.anatomical_structure OLFACTORY SENSORY NEURONS Female Congenital Hypogonadotropic Hypogonadism HORMONE NEURONS Neural development hormones hormone substitutes and hormone antagonists medicine.medical_specialty endocrine system Heterozygote Adolescent MIGRATION Biology Article 03 medical and health sciences Internal medicine KALLMANN-SYNDROME Genetics medicine Animals Humans Nerve Growth Factors MUTATIONS Hypogonadism medicine.disease GENE Olfactory bulb DELETIONS 030104 developmental biology Endocrinology CELLS Mutation Neuron 3111 Biomedicine 030217 neurology & neurosurgery |
| Zdroj: | Am J Hum Genet |
| Popis: | 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 x 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. |
| Databáze: | OpenAIRE |
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