Skip to Main content Skip to Navigation
Journal articles

Identification of a missense variant in CLDN2 in obstructive azoospermia

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.
Document type :
Journal articles
Complete list of metadata

https://hal-pasteur.archives-ouvertes.fr/pasteur-03263628
Contributor : Ken Mcelreavey Connect in order to contact the contributor
Submitted on : Thursday, June 17, 2021 - 2:30:38 PM
Last modification on : Saturday, June 19, 2021 - 3:38:34 AM

Identifiers

Collections

Citation

Masomeh Askari, Razieh Karamzadeh, Naser Ansari-Pour, Mohammad Hossein Karimi-Jafari, Navid Almadani, et al.. Identification of a missense variant in CLDN2 in obstructive azoospermia. Journal of Human Genetics, Nature Publishing Group, 2019, 64 (10), pp.1023-1032. ⟨10.1038/s10038-019-0642-0⟩. ⟨pasteur-03263628⟩

Share

Metrics

Record views

24