HGNC Approved Gene Symbol: CLDN14
Cytogenetic location: 21q22.13 Genomic coordinates (GRCh38) : 21:36,460,621-36,576,569 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.13 | Deafness, autosomal recessive 29 | 614035 | Autosomal recessive | 3 |
The CLDN14 gene encodes claudin-14, which belongs to the claudin family of proteins that polymerize into tight junction fibrils and play a role in selective paracellular permeability. CLDN14 is expressed in the inner ear, where it increases transepithelial resistance by decreasing cation permeability, particularly for potassium (Ben-Yosef et al., 2003; summary by Lee et al., 2012).
By sequencing the long arm of chromosome 21, Hattori et al. (2000) identified the CLDN14 gene. Using RACE, Wilcox et al. (2001) amplified a cDNA encoding CLDN14 from human liver cDNA. Comparison of the genomic chromosome 21 sequence with the cDNA sequence indicated that the CLDN14 gene contains 3 exons, and the authors identified 2 splice isoforms, one with and the other without exon 2. Northern blot analysis detected CLDN14 expression in liver and kidney. In situ hybridization and immunofluorescence studies revealed mouse Cldn14 expression in the sensory epithelium of the organ of Corti.
Wattenhofer et al. (2005) detected 3 hitherto undescribed exons of CLDN14, for a total of 7. Six of these are in the 5-prime untranslated region.
Wattenhofer et al. (2005) stated that a total of 5 alternative transcripts of the CLDN14 gene had been identified to that time.
By sequence analysis of chromosome 21q, Hattori et al. (2000) mapped the CLDN14 gene to 21q22.3.
Autosomal Recessive Deafness 29
In 2 consanguineous Pakistani families with autosomal recessive nonsyndromic deafness mapping to 21q22.1 (DFNB29; 614035), Wilcox et al. (2001) identified 2 homozygous mutations in the CLDN14 gene: a 1-bp deletion (398delT; 605608.0001) in 1 family and a val85-to-asp missense mutation (605608.0002) in the other.
In affected members of 4 consanguineous Pakistani families with DFNB29, Lee et al. (2012) identified 4 different homozygous mutations in the CLDN14 gene (605608.0002; 605608.0004-605608.0006). Functional studies of the variants were not performed. The families were ascertained from a larger cohort of 353 consanguineous Pakistani families with autosomal recessive nonsyndromic hearing loss who underwent linkage scans.
Susceptibility to Kidney Stones
Thorleifsson et al. (2009) conducted a genomewide association study of 3,773 cases with radiopaque kidney stones (nephrolithiasis; see 167030) and 42,510 controls from Iceland and the Netherlands. They found common, synonymous variants in the CLDN14 gene on chromosome 21q22.13 that associated with kidney stones (odds ratio = 1.25, P = 4.0 x 10(-12) for the C allele of rs219780). Approximately 62% of the general Northern European population is homozygous for this variant and is estimated to have a 1.64 times greater risk of developing the disease compared to noncarriers. This variant was found to have 27 to 30% population-attributable risk for the incidence of kidney stones among northern Europeans. The CLDN14 gene is expressed in the kidney and regulates paracellular permeability at epithelial tight junctions. The same variants were found to associate with reduced bone mineral density at the hip (P = 0.00039) and spine (P = 0.0077).
To explore the role of claudin-14 in the inner ear and in other organs, Ben-Yosef et al. (2003) created a mouse model by a targeted deletion of Cldn14. In Cldn14-lacZ heterozygous mice, beta-galactosidase activity was detected in cochlear inner and outer hair cells and supporting cells, in the collecting ducts of the kidney, and around the lobules of the liver. Cldn14-null mice had a normal endocochlear potential but were deaf due to rapid degeneration of cochlear outer hair cells, followed by slower degeneration of the inner hair cells. Monolayers of MDCK cells expressing claudin-14 showed a 6-fold increase in the transepithelial electrical resistance by decreasing paracellular permeability for cations. In wildtype mice, claudin-14 was immunolocalized at hair cell and supporting cell tight junctions. The authors suggested that the tight junction complex at the apex of the reticular lamina may require claudin-14 as a cation-restrictive barrier to maintain the proper ionic composition of the fluid surrounding the basolateral surface of outer hair cells.
In a consanguineous Pakistani family (PKSN6) with autosomal recessive nonsyndromic deafness-29 (DFNB29; 614035), Wilcox et al. (2001) identified a 1-bp deletion (T) at nucleotide 398 of the CLDN14 gene. This frameshift was predicted to cause premature translation termination 69 nucleotides later, after the substitution of 23 incorrect amino acids and the loss of almost half of the predicted protein.
In a consanguineous Pakistani family (PKSR9a) with autosomal recessive nonsyndromic deafness-29 (DFNB29; 614035), Wilcox et al. (2001) identified a T-to-A transversion at nucleotide 254 of the CLDN14 gene, resulting in a val85-to-asp (V85D) mutation. Val85 is conserved among 12 of the 20 claudins, while isoleucine is present among 5 claudins, and the remaining 3 claudins have either a cysteine or proline at this position. Aspartic acid at position 85 was predicted to affect hydrophobicity and disrupt the predicted secondary structures in transmembrane domain 2.
Wattenhofer et al. (2005) found that ectopic expression in L mouse fibroblasts of wildtype CLDN14 protein induced the formation of tight junctions, while the V85D mutant failed to localize to the plasma membrane and to form such junctions.
In affected members of a consanguineous Pakistani family (family 4306) with DFNB29, Lee et al. (2012) identified a homozygous c.254T-A transversion in the CLDN14 gene, resulting in a V85D substitution at a highly conserved residue in the second transmembrane domain. The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family and was not found in 400 Pakistani control chromosomes. Functional studies were not performed.
Through a screen of 183 Spanish and Greek patients with sporadic nonsyndromic deafness, Wattenhofer et al. (2005) identified a gly101-to-arg (G101R) mutation (301G-A) in the CLDN14 gene in a patient from the Greek cohort (K126) with autosomal recessive nonsyndromic deafness-29 (DFNB29; 614035). To investigate the mechanism linking alterations in CLDN14 to the degeneration of hair cells, possibly due to cation overload, observed in the murine model, Wattenhofer et al. (2005) compared the ability of wildtype and missense mutant CLDN14 to form tight junctions. Ectopic expression in L mouse fibroblasts of wildtype CLDN14 protein induced the formation of tight junctions, while both the V85D (605608.0002) and G101R mutants failed to form such junctions. However, the 2 mutant proteins differed in their ability to localize at the plasma membrane. The results indicated that the ability of CLDN14 to be recruited to these junctions is crucial for the hearing process.
In affected members of a consanguineous Pakistani family (family 4158) with autosomal recessive nonsyndromic deafness-29 (DFNB29; 614035), Lee et al. (2012) identified a homozygous c.167G-A transition in the CLDN14 gene, resulting in a trp56-to-ter (W56X) substitution in the first extracellular loop. The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family and was not found in 400 Pakistani control chromosomes. Functional studies were not performed.
In affected members of a consanguineous Pakistani family (family 4209) with autosomal recessive nonsyndromic deafness-29 (DFNB29; 614035), Lee et al. (2012) identified a homozygous c.242G-A transition in the CLDN14 gene, resulting in an arg81-to-his (R81H) substitution at a conserved residue in the first extracellular loop. The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family and was not found in 400 Pakistani control chromosomes. Functional studies were not performed.
In affected members of a consanguineous Pakistani family (family 4413) with autosomal recessive nonsyndromic deafness-29 (DFNB29; 614035), Lee et al. (2012) identified a homozygous c.694G-A transition in the CLDN14 gene, resulting in a gly232-to-arg (G232R) substitution at a conserved residue in the C terminus. The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family and was not found in 400 Pakistani control chromosomes. Functional studies were not performed.
Ben-Yosef, T., Belyantseva, I. A., Saunders, T. L., Hughes, E. D., Kawamoto, K., Van Itallie, C. M., Beyer, L. A., Halsey, K., Gardner, D. J., Wilcox, E. R., Rasmussen, J., Anderson, J. M., Dolan, D. F., Forge, A., Raphael, Y., Camper, S. A., Friedman, T. B. Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Hum. Molec. Genet. 12: 2049-2061, 2003. [PubMed: 12913076] [Full Text: https://doi.org/10.1093/hmg/ddg210]
Hattori, M., Fujiyama, A., Taylor, T. D., Watanabe, H., Yada, T., Park, H.-S., Toyoda, A., Ishii, K., Totoki, Y., Choi, D.-K., Groner, Y., Soeda, E., and 52 others. The DNA sequence of human chromosome 21. Nature 405: 311-319, 2000. Note: Erratum: Nature: 407: 110 only, 2000. [PubMed: 10830953] [Full Text: https://doi.org/10.1038/35012518]
Lee, K., Ansar, M., Andrade, P. B., Khan, B., Santos-Cortez, R. L. P., Ahmad, W., Leal, S. M. Novel CLDN14 mutations in Pakistani families with autosomal recessive non-syndromic hearing loss. Am. J. Med. Genet. 158A: 315-321, 2012. [PubMed: 22246673] [Full Text: https://doi.org/10.1002/ajmg.a.34407]
Thorleifsson, G., Holm, H., Edvardsson, V., Walters, G. B., Styrkarsdottir, U., Gudjartsson, D. F., Sulem, P., Halldorsson, B. V., de Vegt, F., d'Ancona, F. C. H., den Heijer, M., Franzson, L., and 12 others. Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density. Nature Genet. 41: 926-930, 2009. [PubMed: 19561606] [Full Text: https://doi.org/10.1038/ng.404]
Wattenhofer, M., Reymond, A., Falciola, V., Charollais, A., Caille, D., Borel, C., Lyle, R., Estivill, X., Petersen, M. B., Meda, P., Antonarakis, S. E. Different mechanisms preclude mutant CLDN14 proteins from forming tight junctions in vitro. Hum. Mutat. 25: 543-549, 2005. [PubMed: 15880785] [Full Text: https://doi.org/10.1002/humu.20172]
Wilcox, E. R., Burton, Q. L., Naz, S., Riazuddin, S., Smith, T. N., Ploplis, B., Belyatseva, I., Ben-Yosef, T., Liburd, N. A., Morell, R. J., Kachar, B., Wu, D. K., Griffith, A. J., Riazuddin, S., Friedman, T. B. Mutations in the gene encoding tight junction claudin-14 cause recessive deafness DFNB29. Cell 104: 165-172, 2001. [PubMed: 11163249] [Full Text: https://doi.org/10.1016/s0092-8674(01)00200-8]