identification of a missense variant in cldn2 in obstructive azoospermia
| Autor: | Mehdi Totonchi, Razieh Karamzadeh, Naser Ansari-Pour, Masomeh Askari, Mohammad Ali Sadighi Gilani, Anahita Mohseni Meybodi, Anu Bashamboo, Mehdi Sadeghi, Ahmad Vosough Taghi Dizaj, Hamid Gourabi, Ken McElreavey, Navid Almadani, Mohammad Hossein Karimi-Jafari |
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| Přispěvatelé: | Royan Institute for Reproductive Biomedicine [Tehran, Iran], Academic Center for Education, Culture and Research (ACECR), Royan Institute for Stem Cell Biology and Technology, University of Tehran, University of Oxford [Oxford], Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported in part by a grant from the Iran National Science Foundation (INSF), Royan Institute and the Institut Pasteur, Paris. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., University of Oxford, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Models Molecular 0301 basic medicine Molecular biology MESH: Pedigree [SDV]Life Sciences [q-bio] Mutation Missense Obstructive azoospermia MESH: Claudins 030105 genetics & heredity Biology MESH: Phenotype 03 medical and health sciences MESH: Whole Exome Sequencing Mutant protein Exome Sequencing medicine Genetics Humans Missense mutation Pathogenicity Family Genetics(clinical) MESH: Family Genetics (clinical) Tight junction Azoospermia MESH: Mutation Missense MESH: Humans Genital tract medicine.disease Phenotype MESH: Male Pedigree 3. Good health 030104 developmental biology Male Genital Tract Claudins MESH: Azoospermia Identification (biology) MESH: Models Molecular |
| Zdroj: | Journal of Human Genetics Journal of Human Genetics, Nature Publishing Group, 2019, 64 (10), pp.1023-1032. ⟨10.1038/s10038-019-0642-0⟩ Journal of Human Genetics, 2019, 64 (10), pp.1023-1032. ⟨10.1038/s10038-019-0642-0⟩ Microsoft Academic Graph Datacite |
| ISSN: | 1434-5161 1435-232X |
| DOI: | 10.1038/s10038-019-0642-0⟩ |
| Popis: | International audience; Obstructive azoospermia (OA), defined as an obstruction in any region of the male genital tract, accounts for 40% of all azoospermia cases. Of all OA cases, ~30% are thought to have a genetic origin, however, hitherto, the underlying genetic etiology of the majority of these cases remain unknown. To address this, we took a family-based whole-exome sequencing approach to identify causal variants of OA in a multiplex family with epidydimal obstruction. A novel gain-of-function missense variant in CLDN2 (c.481G>C; p.Gly161Arg) was found to co-segregate with the phenotype, consistent with the X-linked inheritance pattern observed in the pedigree. To assess the pathogenicity of this variant, the wild and mutant protein structures were modeled and their potential for strand formation in multimeric form was assessed and compared. The results showed that dimeric and tetrameric arrangements of Claudin-2 were not only reduced, but were also significantly altered by this single residue change. We, therefore, envisage that this amino acid change likely forms a polymeric discontinuous strand, which may lead to the disruption of tight junctions among epithelial cells. This missense variant is thus likely to be responsible for the disruption of the blood-epididymis barrier, causing dislodged epithelial cells to clog the genital tract, hence causing OA. This study not only sheds light on the underlying pathobiology of OA, but also provides a basis for more efficient diagnosis in the clinical setting. |
| Databáze: | OpenAIRE |
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