CLDN25 (claudin 25) is a tight junction protein that contributes to the regulation of intercellular barrier function through calcium-independent cell-adhesion activity [UniProt]. Unlike canonical claudins, CLDN25 does not contain the conserved C-terminal ZO-1 binding motif but requires its C-terminal region for proper junctional localization in a ZO-1-independent manner 1. At the blood-brain barrier, CLDN25 is highly expressed in vivo alongside other claudins but functions distinctly: rather than tightening the paracellular barrier, it contributes to proper tight junction strand morphology 2. Intriguingly, cellular knockout of CLDN25 increases tight junction integrity while paradoxically driving increased solute movement between cells, suggesting a "decoy claudin" mechanism that modulates dynamic changes in cell-cell adhesion capacity 1. Clinical significance: A de novo heterozygous missense variant (c.745G>C, p.A249P) in CLDN25 was identified in a patient with Pelizaeus-Merzbacher-like leukodystrophy presenting with delayed motor development, seizures, and dystonia 1. This mutation prevents proper junctional localization and likely causes haploinsufficiency. Additionally, CLDN25 variants have been associated with diabetic retinopathy risk in machine learning prediction models 3, suggesting broader relevance to vascular barrier dysfunction.