Loss-of-function variants in SEMA3F and PLXNA3 encoding semaphorin-3F and its receptor plexin-A3 respectively cause idiopathic hypogonadotropic hypogonadism
| Autor: | Esra niz P. De Cakir, Eda Mengen, Olcay Evliyaoğlu, Paolo Giacobini, A. Kemal Topaloglu, Ihsan Turan, Gaspard Delpouve, Gamze Akkus, Feyza Darendeliler, Aysegul Yuksel, Asli rya De Kardelen, Fatih Gurbuz, Aydilek Dagdeviren Cakir, Sebahat Yılmaz Ağladıoğlu, Semine Özdemir Dilek, Bilgin Yüksel, Gaetan Ternier, Bahar Ozcabi, Hamdi Cihan Emeksiz, Emregul Isik, Leman Damla Kotan |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Vomeronasal organ Kallmann syndrome Nerve Tissue Proteins Receptors Cell Surface Olfaction Semaphorins Article 03 medical and health sciences 0302 clinical medicine Semaphorin Olfactory nerve Hypogonadotropic hypogonadism Internal medicine medicine Humans Genetics (clinical) 030304 developmental biology 0303 health sciences biology Hypogonadism Plexin Membrane Proteins medicine.disease 3. Good health body regions medicine.anatomical_structure Endocrinology HEK293 Cells biology.protein Terminal nerve Cell Adhesion Molecules 030217 neurology & neurosurgery |
| Zdroj: | Genet Med Genetics in Medicine |
| ISSN: | 1530-0366 |
| Popis: | Purpose Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent puberty and subsequent infertility due to gonadotropin-releasing hormone (GnRH) deficiency. IHH can be accompanied by normal or compromised olfaction (Kallmann syndrome). Several semaphorins are known potent modulators of GnRH, olfactory, and vomeronasal system development. In this study, we investigated the role of Semaphorin-3F signaling in the etiology of IHH. Methods We screened 216 IHH patients by exome sequencing. We transiently transfected HEK293T cells with plasmids encoding wild type (WT) or corresponding variants to investigate the functional consequences. We performed fluorescent IHC to assess SEMA3F and PLXNA3 expression both in the nasal region and at the nasal/forebrain junction during the early human fetal development. Results We identified ten rare missense variants in SEMA3F and PLXNA3 in 15 patients from 11 independent families. Most of these variants were predicted to be deleterious by functional assays. SEMA3F and PLXNA3 are both expressed along the olfactory nerve and intracranial projection of the vomeronasal nerve/terminal nerve. PLXNA1-A3 are expressed in the early migratory GnRH neurons. Conclusion SEMA3F signaling through PLXNA1-A3 is involved in the guidance of GnRH neurons and of olfactory and vomeronasal nerve fibers in humans. Overall, our findings suggest that Semaphorin-3F signaling insufficiency contributes to the pathogenesis of IHH. |
| Databáze: | OpenAIRE |
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