• PMID: 31320686
• Gene Name: CLDN2
• Condition: Obstructive azoospermia (OA)
• Association: Associated
• Mutation: c.481G>C; p.Gly161Arg
• Population size: 472
• Population details: 3 familial, 469 (400 ancestry-matched Iranian fertile and 69 unrelated men with idiopathic OA)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Identification of a missense variant in CLDN2 in obstructive azoospermia

Askari M, Karamzadeh R, Ansari-Pour N, Karimi-Jafari MH, Almadani N, Sadighi Gilani MA, Gourabi H, Vosough Taghi Dizaj A, Mohseni Meybodi A, Sadeghi M, Bashamboo A, McElreavey K, Totonchi M.

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. FAU - Askari, Masomeh AU - Askari M AD - Department of Genetics at Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. FAU - Karamzadeh, Razieh AU - Karamzadeh R AD - Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. FAU - Ansari-Pour, Naser AU - Ansari-Pour N AD - Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran. AD - Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7LF, UK. FAU - Karimi-Jafari, Mohammad Hossein AU - Karimi-Jafari MH AD - Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. FAU - Almadani, Navid AU - Almadani N AD - Department of Genetics at Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. FAU - Sadighi Gilani, Mohammad Ali AU - Sadighi Gilani MA AD - Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. FAU - Gourabi, Hamid AU - Gourabi H AD - Department of Genetics at Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. FAU - Vosough Taghi Dizaj, Ahmad AU - Vosough Taghi Dizaj A AD - Department of Reproductive Imaging, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. FAU - Mohseni Meybodi, Anahita AU - Mohseni Meybodi A AD - Department of Genetics at Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. FAU - Sadeghi, Mehdi AU - Sadeghi M AD - Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran. AD - School of Biological Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran. FAU - Bashamboo, Anu AU - Bashamboo A AD - Human Developmental Genetics, Institute Pasteur, Paris, France. FAU - McElreavey, Ken AU - McElreavey K AD - Human Developmental Genetics, Institute Pasteur, Paris, France. kenneth.mcelreavey@pasteur.fr.