CLDN5 and Schizophrenia

Claudin-5 (HGNC:2047) is a critical tight junction protein predominantly expressed at the blood-brain barrier. Recent genetic investigations have implicated variants in this gene as contributory to schizophrenia (MONDO_0005090). Two independent family-based studies provide the primary evidence for this association. In one study, 176 Chinese family trios demonstrated significant transmission disequilibrium for a 3'-untranslated region SNP in CLDN5 (PMID:15363474). A second study, evaluating 131 British family trios, reported that the combination of CLDN5 and PLA2G4A risk alleles resulted in a stronger association with schizophrenia (PMID:16181776).

The combined data from these investigations involve a total of 307 affected probands. Although the transmission disequilibrium test (TDT) results reach statistical significance, in-depth familial segregation beyond the proband remains limited. This evidence provides a moderate level of support for a gene-disease relationship, as the studies have detected an association signal without extensive segregation in additional affected relatives.

Functional studies further substantiate the potential role of CLDN5 in schizophrenia. Experimental work demonstrates that modulation of claudin-5 can reversibly alter blood-brain barrier permeability, which may influence the central nervous system environment relevant to neuropsychiatric disorders (PMID:29421550). In addition, in silico modelling and molecular dynamics simulations support the notion that specific CLDN5 mutations (e.g. c.178G>A (p.Gly60Arg)) can alter paracellular ion selectivity, lending mechanistic plausibility to its involvement in disease (PMID:37138900).

The genetic evidence, while derived from robust family-based studies employing the transmission disequilibrium test, remains moderate in strength due to the limited segregation analysis. Conversely, the functional studies provide independent experimental confirmation that disruption in CLDN5 function may perturb blood-brain barrier integrity, a factor potentially linked to schizophrenia pathogenesis.

Collectively, the integration of both genetic and experimental data supports a moderate association between CLDN5 variants and schizophrenia. While additional investigations may further refine this relationship, the current evidence is valuable for diagnostic decision‑making and underpins novel therapeutic strategies targeting blood‑brain barrier modulation.

Key Take‑home Sentence: The combined genetic and functional evidence indicates that alterations in CLDN5 contribute moderately to schizophrenia susceptibility, emphasizing its potential clinical utility as a biomarker and therapeutic target.

References

• European Psychiatry • 2004 • The CLDN5 locus may be involved in the vulnerability to schizophrenia PMID:15363474
• Prostaglandins, leukotrienes, and essential fatty acids • 2005 • A study of the combined effect of the CLDN5 locus and the genes for the phospholipid metabolism pathway in schizophrenia PMID:16181776
• Biomaterials • 2018 • Reversible opening of the blood-brain barrier by claudin-5-binding variants of Clostridium perfringens enterotoxin's claudin-binding domain PMID:29421550
• Computational and structural biotechnology journal • 2023 • The impact of pathogenic and artificial mutations on Claudin-5 selectivity from molecular dynamics simulations PMID:37138900

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