Detailed Clinical Features of Deafness Caused by a Claudin-14 Variant

Abstract

Tight junctions are cellular junctions that play a major role in the epithelial barrier function. In the inner ear, claudins, occludin, tricellulin, and angulins form the bicellular or tricellular binding of membrane proteins. In these, one type of claudin gene, CLDN14, was reported to be responsible for human hereditary hearing loss, DFNB29. Until now, nine pathogenic variants have been reported, and most phenotypic features remain unclear. In the present study, genetic screening for 68 previously reported deafness causative genes was carried out to identify CLDN14 variants in a large series of Japanese hearing loss patients, and to clarify the prevalence and clinical characteristics of DFNB29 in the Japanese population. One patient had a homozygous novel variant (c.241C>T: p.Arg81Cys) (0.04%: 1/2549). The patient showed progressive bilateral hearing loss, with post-lingual onset. Pure-tone audiograms indicated a high-frequency hearing loss type, and the deterioration gradually spread to other frequencies. The patient showed normal vestibular function. Cochlear implantation improved the patient’s sound field threshold levels, but not speech discrimination scores. This report indicated that claudin-14 is essential for maintaining the inner ear environment and suggested the possible phenotypic expansion of DFNB29. This is the first report of a patient with a tight junction variant receiving a cochlear implantation.

The genetic etiology of hearing loss in Japan revealed by the social health insurance-based genetic testing of 10K patients

“…Meanwhile, both the number of DNA samples and detailed clinical data are increasing, and genetic and clinical data from over 10,000 patients has been collected from 102 collaborative centers. Based on this large-cohort data, we have published a series of studies demonstrating the mutational spectrum and clinical features caused by the representative deafness genes, including GJB2 (Tsukada et al 2010), CDH23 (Miyagawa et al 2012), KCNQ4 (Naito et al 2013), OTOF (Iwasa et al 2013(Iwasa et al , 2019, mitochondrial 1555A > G and 3243A > G (Yano et al 2014), SLC26A4 (Miyagawa et al 2014), LRTOMT (Ichinose et al 2015), GRXCR1 (Mori et al 2015a), PTPRQ (Sakuma et al 2015), COCH (Tsukada et al 2015a), TMPRSS3 (Miyagawa et al 2015d), STRC (Moteki et al 2016;Yokota et al 2019), LOXHD1 (Mori et al 2015b;Maekawa et al 2019), ACTG1 (Miyagawa et al 2015b;Miyajima et al 2020), MYO15A (Miyagawa et al 2015a), POU4F3 (Kitano et al 2017), WFS1 (Kobayashi et al 2018), CLDN14 (Kitano et al 2019), EYA4 (Shinagawa et al 2020a, b), TECTA (Yasukawa et al 2019), OTOA (Sugiyama et al 2019), and MYO6 (Miyagawa et al 2015c;Oka et al, 2020). These studies were performed between 2010 and 2020.…”

Autosomal recessive non‐syndromic hearing loss genes in Pakistan during the previous three decades

“…CLDN14 , also known as DFNB29, encodes the claudin‐14 protein, an essential membrane protein forming tight junctions in the inner ear 15 . These tight junctions are crucial for compartmentalizing the endolymphatic and perilymphatic fluid compartments, maintaining cell polarity, and regulating intercellular permeability to solutes, ions, and water 80 . CLDN14 is expressed in the inner and outer hair cells, supporting cells, and Reissner's membrane 81 .…”

“…It plays a crucial role in maintaining ion homeostasis and calcium levels in the endolymph and perilymph fluids, which is essential for the MET process of cochlear hair cells 82 . MET is initiated by the opening of cation channels near the tip of the stereocilia and requires ion homeostasis to maintain ion gradients for preservation of the endocochlear potential 80 . While the endocochlear potential in Cldn14‐ null mice has been determined as normal, rapid degeneration of outer hair cells and progressive slower degeneration of IHCs is thought to be due to the compromised tight junction barrier 83 .…”

“… 15 These tight junctions are crucial for compartmentalizing the endolymphatic and perilymphatic fluid compartments, maintaining cell polarity, and regulating intercellular permeability to solutes, ions, and water. 80 CLDN14 is expressed in the inner and outer hair cells, supporting cells, and Reissner's membrane. 81 It plays a crucial role in maintaining ion homeostasis and calcium levels in the endolymph and perilymph fluids, which is essential for the MET process of cochlear hair cells.…”

Special Issue on “The Tight Junction and Its Proteins: More than Just a Barrier”

“…Several loss-of-function mutations in TJ proteins have been linked to deafness. A novel variant of claudin-14, besides nine others, is linked to the phenotypic expansion of hereditary hearing loss, DFNB2 [ 28 ].…”