ArticleJournal of human genetics2019
Identification of a missense variant in CLDN2 in obstructive azoospermia.
Article in Journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Tight junction structure, assembly and (dys)function.Nature reviews. Molecular cell biology · 2026Review
- Claudin proteins as emerging therapeutic targets for solid tumours.Nature reviews. Cancer · 2026Review
- Paracellular Transport and Renal Tubule Calcium Handling: Emerging Roles in Kidney Stone Disease.Journal of the American Society of Nephrology : JASN · 2024Review
- Claudin 1, 4, 6 and 18 isoform 2 as targets for the treatment of cancer (Review).International journal of molecular medicine · 2024Review
- Review of childhood genetic nephrolithiasis and nephrocalcinosis.Frontiers in genetics · 2024Review
- The role of claudins in homeostasis.Nature reviews. Nephrology · 2023Review
- The CLDN5 gene at the blood-brain barrier in health and disease.Fluids and barriers of the CNS · 2023Review
- Recurrent de novo mutations in CLDN5 induce an anion-selective blood-brain barrier and alternating hemiplegia.Brain : a journal of neurology · 2022Article
- The genetic causes of male infertility: a Middle East and North Africa perspective.F1000Research · 2022Review
- Multiscale modelling of claudin-based assemblies: A magnifying glass for novel structures of biological interfaces.Computational and structural biotechnology journal · 2022Review
- The X chromosome and male infertility.Human genetics · 2021Review
- Strategies for whole-exome sequencing analysis in a case series study of familial male infertility.International journal of reproductive biomedicine · 2020Article
- Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease.The Journal of clinical investigation · 2020Article
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Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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