Variants of human
            <i>CLDN9</i>
            cause mild to profound hearing loss

Ramzan, Memoona; Philippe, Christophe; Belyantseva, Inna A.; Nakano, Yoko; Fenollar–Ferrer, Cristina; Tona, Risa; Yousaf, Rizwan; Basheer, Rasheeda; Imtiaz, Ayesha; Faridi, Rabia; Munir, Zunaira; Idrees, Hafiza; Salman, Midhat; Nambot, Sophie; Vitobello, Antonio; Kartti, Souad; Zarrik, Oumaima; Witmer, P. Dane; Sobreria, Nara; Ibrahimi, Azeddine; Bánfi, Botond; Moutton, Sébastien; Friedman, Thomas B.; Naz, Sadaf

doi:10.1002/humu.24260

Cited by 5 publications

(4 citation statements)

References 40 publications

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“…Mutations in TMPRSS3 , one of the MASPs, cause hearing loss due to hair cell degeneration ( Scott et al, 2001 ; Fasquelle et al, 2011 ). As loss of claudins in the inner ear causes the degenerative death of cochlear hair cells, resulting in congenital hearing loss in humans and mice ( Wilcox et al, 2001 ; Ben-Yosef et al, 2003 ; Kitajiri et al, 2004 ; Nakano et al, 2009 ; Ramzan et al, 2021 ), TMPRSS3 may also be involved in the formation or maintenance of TJs in the cochlear sensory epithelium.…”

Section: Discussionmentioning

confidence: 99%

EpCAM proteolysis and release of complexed claudin-7 repair and maintain the tight junction barrier

Higashi

Saitō

Fukazawa

et al. 2022

Journal of Cell Biology

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TJs maintain the epithelial barrier by regulating paracellular permeability. Since TJs are under dynamically fluctuating intercellular tension, cells must continuously survey and repair any damage. However, the underlying mechanisms allowing cells to sense TJ damage and repair the barrier are not yet fully understood. Here, we showed that proteinases play an important role in the maintenance of the epithelial barrier. At TJ break sites, EpCAM–claudin-7 complexes on the basolateral membrane become accessible to apical membrane-anchored serine proteinases (MASPs) and the MASPs cleave EpCAM. Biochemical data and imaging analysis suggest that claudin-7 released from EpCAM contributes to the rapid repair of damaged TJs. Knockout (KO) of MASPs drastically reduced barrier function and live-imaging of TJ permeability showed that MASPs-KO cells exhibited increased size, duration, and frequency of leaks. Together, our results reveal a novel mechanism of TJ maintenance through the localized proteolysis of EpCAM at TJ leaks, and provide a better understanding of the dynamic regulation of epithelial permeability.

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Section: Discussionmentioning

confidence: 99%

EpCAM proteolysis and release of complexed claudin-7 repair and maintain the tight junction barrier

Higashi

Saitō

Fukazawa

et al. 2022

Journal of Cell Biology

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“…Waardenburg syndrome due to MTIF or PAX3 variants has also been reported to manifest variable type of hearing loss, including single side deafness or asymmetric hearing loss (Kim et al 2015; Wang et al 2021). In addition, biallelic GJB2 , SLC26A4 , and CLDN9 (Ramzan et al 2021) recessive variants may cause asymmetric non-syndrome hearing loss. Specifically, the GJB2 c.235delC homozygous variant has been reported to account for a significant proportion of asymmetric hearing loss (Guo et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Novel Molecular Genetic Etiology of Asymmetric Hearing Loss: Autosomal-Dominant LMX1A Variants

et al. 2022

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Introduction: Sensorineural hearing loss is the most common sensory disorder in humans. Genetic analyses have greatly increased our understanding of the pathogenic mechanisms in play. Thus, characterization of audiologic phenotypes by the genetic etiology may aid elucidation of the etiologies of certain types of inherited hearing loss. Further, delineation of specific audiologic phenotypes based on the genetic etiology aids our understanding of some types of inherited hearing loss in terms of the prediction of clinical course, revelation of genotype-phenotype correlations, and application of appropriate audiologic rehabilitation. Here, we describe the interesting audiologic characteristics of LMX1A-associated deafness, which revealed significant asymmetry between two ears.Methods: Among 728 probands of which genomic DNA went through exome sequencing regardless of any specific audiologic phenotypes, probands for which exome sequencing was performed and a causative LMX1A variant was found were all included. Five LMX1A-associated DFNA7 families (approximately 0.7%), the pedigrees of whom indicated autosomal-dominant hearing loss, were identified, and segregation was studied using Sanger sequencing. The affected individuals underwent comprehensive evaluations, including medical history reviews, physical examinations, imaging, and auditory phenotyping. We functionally characterized the novel LMX1A variants via computational structural modeling and luciferase reporter assays.Results: Among 728 probands of which genomic DNA went through exome sequencing, we identified four novel LMX1A heterozygous variants related to DFNA7 (c.622C>T:p.Arg208*, c.719A>G:p.Gln240Arg, c.721G>A:p.Val241Met, and c.887dup:p.Gln297Thrfs*41) and one harboring a de novo heterozygous missense LMX1A variant (c.595A>G;p. Arg199Gly) previously reported. It is important to note that asymmetric hearing loss was identified in all probands and most affected individuals, although the extent of asymmetry varied. Structural modeling revealed that the two missense variants, p.Gln240Arg and p.Val241Met, affected conserved residues of the homeodomain, thus attenuating LMX1A-DNA interaction. In addition, Arg208*-induced premature termination of translation destroyed the structure of the LMX1A protein, including the DNA-binding homeodomain, and p.Gln297Thrfs*41 led to the loss of the C-terminal helix involved in LIM2 domain interaction. Compared with the wild-type protein, all mutant LMX1A proteins had significantly reduced transactivation efficiency, indicating that the ability to elicit transcription of the downstream target genes of LMX1A was severely compromised. Thus, in line with the American College of Medical Genetics and Genomics guideline specified to genetic hearing loss, the four novel LMX1A variants were identified as "pathogenic" (p.Arg208* and p.Gln297Thrfs*41), "likely pathogenic" (p.Val241Met), and as a "variant of uncertain significance'' (p.Gln240Arg). Conclusion:For the first time, we suggest that LMX1A is one of the candidate genes which, i...

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“… CLDN-1 (R81H) R81 Very High Mis-localization due to the structural instability [ 144 ] CLDN-2 (G161R) G161 Very high In silico docking study indicates it may affect oligomer formations [ 233 ] CLDN-9 (E159K) E159 Very High Incorporation into the TJs or barrier-forming ability were not impaired. But this position needs for cis-interaction [ 234 ] CLDN-10a (R78G) R81 Very High Mis-localization due to the structural instability [ 143 ] CLDN-10b (N48K) G48 High TJs were not formed correctly due to the disturbance of classic CLDN signature [ 235 ] CLDN-10b (D73N) S74 Low Incorporation into the TJs was partially impaired by attenuation of CLDN-10b specific intra-molecule interaction [ 148 , 236 ] CLDN-10b (P149R) P150 Very High Incorporation into the TJs was partially impaired by impaired cis-oligomerization CLDN-10b (S131L) A132 Low Mis-localization [ 237 ] CLDN-10b (G165A) G167 Very high Incorporation into the TJs was partially impaired and trans-interaction ability was clearly attenuated [ 238 <...…”

Section: The Mutagenesis- and Structure-based Studies To Characterize...mentioning

confidence: 99%

The CLDN5 gene at the blood-brain barrier in health and disease

Hashimoto

Münnich

Campbell

2023

Fluids Barriers CNS

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The CLDN5 gene encodes claudin-5 (CLDN-5) that is expressed in endothelial cells and forms tight junctions which limit the passive diffusions of ions and solutes. The blood–brain barrier (BBB), composed of brain microvascular endothelial cells and associated pericytes and end-feet of astrocytes, is a physical and biological barrier to maintain the brain microenvironment. The expression of CLDN-5 is tightly regulated in the BBB by other junctional proteins in endothelial cells and by supports from pericytes and astrocytes. The most recent literature clearly shows a compromised BBB with a decline in CLDN-5 expression increasing the risks of developing neuropsychiatric disorders, epilepsy, brain calcification and dementia. The purpose of this review is to summarize the known diseases associated with CLDN-5 expression and function. In the first part of this review, we highlight the recent understanding of how other junctional proteins as well as pericytes and astrocytes maintain CLDN-5 expression in brain endothelial cells. We detail some drugs that can enhance these supports and are being developed or currently in use to treat diseases associated with CLDN-5 decline. We then summarise mutagenesis-based studies which have facilitated a better understanding of the physiological role of the CLDN-5 protein at the BBB and have demonstrated the functional consequences of a recently identified pathogenic CLDN-5 missense mutation from patients with alternating hemiplegia of childhood. This mutation is the first gain-of-function mutation identified in the CLDN gene family with all others representing loss-of-function mutations resulting in mis-localization of CLDN protein and/or attenuated barrier function. Finally, we summarize recent reports about the dosage-dependent effect of CLDN-5 expression on the development of neurological diseases in mice and discuss what cellular supports for CLDN-5 regulation are compromised in the BBB in human diseases.

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Variants of human CLDN9 cause mild to profound hearing loss

Cited by 5 publications

References 40 publications

EpCAM proteolysis and release of complexed claudin-7 repair and maintain the tight junction barrier

EpCAM proteolysis and release of complexed claudin-7 repair and maintain the tight junction barrier

Novel Molecular Genetic Etiology of Asymmetric Hearing Loss: Autosomal-Dominant LMX1A Variants

The CLDN5 gene at the blood-brain barrier in health and disease

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