CLDN14 – Autosomal Recessive Nonsyndromic Hearing Loss 29

CLDN14 encodes claudin-14, a tight junction protein essential for ionic homeostasis in the inner ear. In a Japanese cohort of hearing loss patients, one unrelated individual with post-lingual progressive bilateral sensorineural hearing loss was homozygous for c.241C>T (p.Arg81Cys), exhibiting high-frequency hearing loss that gradually spread across frequencies while vestibular function remained intact; cochlear implantation improved sound thresholds but not speech discrimination (PMID:31527509). Functional cell-based assays comparing wild-type and missense CLDN14 constructs (p.Val85Asp, p.Gly101Arg) revealed that pathogenic variants fail to form tight junction strands and exhibit impaired plasma membrane recruitment, demonstrating a loss-of-function mechanism consistent with DFNB29 pathology (PMID:15880785).

Although only two probands with recessive missense variants have been reported and no segregation beyond the index case is available, concordant in vitro functional data support pathogenicity. Additional large-scale cohort studies and detailed family analyses are needed to reach conclusive evidence. Key Take-home: CLDN14 variants leading to impaired tight junction formation underlie autosomal recessive nonsyndromic hearing loss 29, informing genetic diagnosis and cochlear implantation prognosis.

References

• International Journal of Molecular Sciences | 2019 | Detailed Clinical Features of Deafness Caused by a Claudin-14 Variant PMID:31527509
• Human Mutation | 2005 | Different mechanisms preclude mutant CLDN14 proteins from forming tight junctions in vitro PMID:15880785

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