HGNC Approved Gene Symbol: RDX
Cytogenetic location: 11q22.3 Genomic coordinates (GRCh38) : 11:110,174,922-110,296,614 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q22.3 | Deafness, autosomal recessive 24 | 611022 | Autosomal recessive | 3 |
Radixin (RDX), a member of the band 4.1 superfamily, has a role in formation of the membrane-associated cytoskeleton by linking actin filaments to the plasma membrane (summary by Khan et al., 2007 and Shearer et al., 2009).
Wilgenbus et al. (1993) cloned and sequenced the human radixin cDNA and found the predicted amino acid sequence for the human protein to be nearly identical to those predicted for radixin in mouse and pig. Wilgenbus et al. (1993) noted that cloning of the murine and porcine radixin cDNAs demonstrated a protein highly homologous to ezrin (123900) and moesin (309845).
By immunocytochemical analysis of isolated inner ear hair cells, Pataky et al. (2004) demonstrated that radixin is expressed at the base of hair bundles in chicken, frog, mouse, and zebrafish. Electron microscopic analysis found labeling in the stereociliary taper and the lower stereociliary shaft, with progressively less labeling toward the top of the hair bundle. Pataky et al. (2004) concluded that radixin may participate in anchoring the 'pointed' ends of actin filaments to the membrane in stereocilia.
Khan et al. (2007) identified 6 alternatively spliced RDX isoforms in human retina and inner eye. The major full-length protein contains 627 amino acids forming 3 known functional domains: an N-terminal FERM domain that localizes the protein to the plasma membrane, a central helical alpha-domain, and a C-terminal actin-binding domain. By immunohistochemical analysis of mouse inner ear, Khan et al. (2007) confirmed the localization of radixin along the length of cochlear hair cell stereocilia and in hair cells of the crista ampullaris at postnatal day 30.
Using antigen-activated T cells, Faure et al. (2004) showed that the ezrin-radixin-moesin (ERM) proteins are rapidly inactivated through a VAV1 (164875)-RAC1 (602048) pathway. The resulting disanchoring of the cortical actin cytoskeleton from the plasma membrane decreased cellular rigidity, leading to more efficient T cell-APC (antigen-presenting cell) conjugate formation. The authors concluded that this pathway favors immunologic synapse formation and the development of an effective immune response.
Wilgenbus et al. (1993) used PCR of Chinese hamster/human somatic cell hybrid DNAs, as well as standard Southern analysis of somatic cell hybrids, to assign the RDX gene to 11q. By fluorescence in situ hybridization, they further localized the gene to 11q23.
Pseudogenes
Wilgenbus et al. (1993) assigned a truncated version of the RDX gene representing a pseudogene (RDXP2) was assigned to Xp21.3. Another pseudogene that seemed to lack introns (RDXP1) was mapped to 11p by Southern and PCR analyses.
Khan et al. (2007) identified 3 respective pathogenic mutations in the RDX gene (179410.0001-179410.0003) in affected members of 3 Pakistani families with autosomal recessive deafness-24 (DFNB24; 611022). The mutations were predicted to disrupt or delete the actin-binding domain of the protein. None of the affected individuals had vestibular dysfunction or hyperbilirubinemia.
The ERM family of proteins crosslink actin filaments and integral membrane proteins. Radixin is the dominant ERM protein in the liver of wildtype mice and is concentrated at bile canalicular membranes (BCM). Kikuchi et al. (2002) showed that Rdx -/- mice are normal at birth, but their serum concentrations of conjugated bilirubin begin to increase gradually around 4 weeks of age, and they show mild liver injury after 8 weeks. This phenotype is similar to human conjugated hyperbilirubinemia in Dubin-Johnson syndrome (237500), which is caused by mutations in the ABCC2 gene (601107), although Dubin-Johnson syndrome is not associated with overt liver injury. In wildtype mice, the protein product of the ABCC2 gene, multidrug resistance protein-2, or MRP2, concentrates at BCMs to secrete conjugated bilirubin into bile. In the BCMs of Rdx -/- mice, Mrp2 is decreased compared with other BCM proteins such as dipeptidyl peptidase IV (CD26; 102720) and P-glycoproteins. In vitro binding studies showed that radixin associates directly with the C-terminal cytoplasmic domain of human MRP2. These findings indicated that radixin is required for secretion of conjugated bilirubin through its support of Mrp2 localization at BCMs.
In the adult mouse, Kitajiri et al. (2004) demonstrated that radixin was enriched in stereocilia of cochlear and vestibular sensory hair cells. Rdx-null mice adult mice were deaf but had no obvious vestibular dysfunction. As the Rdx-null mice grew, ezrin-based cochlear stereocilia progressively degenerated, whereas ezrin-based vestibular stereocilia were maintained normally. Kitajiri et al. (2004) concluded that radixin is indispensable for hearing ability in mice through the maintenance of cochlear stereocilia, but that ezrin can compensate for radixin deficiency in vestibular stereocilia.
In 2 affected sisters from a consanguineous Pakistani family with autosomal recessive deafness-24 (DFNB24; 611022), Khan et al. (2007) identified a homozygous 1732G-A transition in exon 14 of the RDX gene, resulting in an asp578-to-asn (D578N) substitution predicted to disrupt the actin binding domain of radixin. The mutation was not identified in 200 ethnically matched chromosomes.
In 4 affected members of a consanguineous Pakistani family with DFNB24 (611022), Khan et al. (2007) identified a homozygous 1-bp insertion (1404insG) in exon 13 of the RDX gene, resulting in a frameshift and a truncated protein of 486 amino acids that would lack the actin-binding domain. The mutation was not identified in 200 ethnically matched chromosomes.
In affected members of a family with DFNB24 (611022), Khan et al. (2007) identified a homozygous 463C-T transition in exon 5 of the RDX gene, resulting in a gln155-to-ter (Q155X) substitution in the FERM domain. The mutation was not identified in 200 ethnically matched chromosomes.
In 4 affected members of a consanguineous Iranian family with DFNB24 (611022), Shearer et al. (2009) identified a homozygous G-to-A transition in intron 7 of the RDX gene (689+1G-A), predicted to result in premature termination following exon 7 or nonsense-mediated mRNA decay. Affected individuals had congenital onset of severe to profound hearing loss. The mutation was not identified in 53 Iranian and 133 European controls.
Faure, S., Salazar-Fontana, L. I., Semichon, M., Tybulewicz, V. L. J., Bismuth, G., Trautmann, A., Germain, R. N., Delon, J. ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nature Immun. 5: 272-279, 2004. [PubMed: 14758359] [Full Text: https://doi.org/10.1038/ni1039]
Khan, S. Y., Ahmed, Z. M., Shabbir, M. I., Kitajiri, S., Kalsoom, S., Tasneem, S., Shayiq, S., Ramesh, A., Srisailpathy, S., Khan, S. N., Smith, R. J. H., Riazuddin, S., Friedman, T. B., Riazuddin, S. Mutations of the RDX gene cause nonsyndromic hearing loss at the DFNB24 locus. Hum. Mutat. 28: 417-423, 2007. [PubMed: 17226784] [Full Text: https://doi.org/10.1002/humu.20469]
Kikuchi, S., Hata, M., Fukumoto, K., Yamane, Y., Matsui, T., Tamura, A., Yonemura, S., Yamagishi, H., Keppler, D., Tsukita, S., Tsukita, S. Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes. Nature Genet. 31: 320-325, 2002. [PubMed: 12068294] [Full Text: https://doi.org/10.1038/ng905]
Kitajiri, S., Fukumoto, K., Hata, M., Sasaki, H., Katsuno, T., Nakagawa, T., Ito, J., Tsukita, S., Tsukita, S. Radixin deficiency causes deafness associated with progressive degeneration of cochlear stereocilia. J. Cell Biol. 166: 559-570, 2004. [PubMed: 15314067] [Full Text: https://doi.org/10.1083/jcb.200402007]
Pataky, F., Pironkova, R., Hudspeth, A. J. Radixin is a constituent of stereocilia in hair cells. Proc. Nat. Acad. Sci. 101: 2601-2606, 2004. [PubMed: 14983055] [Full Text: https://doi.org/10.1073/pnas.0308620100]
Shearer, A. E., Hildebrand, M. S., Bromhead, C. J., Kahrizi, K., Webster, J. A., Azadeh, B., Kimberling, W. J., Anousheh, A., Nazeri, A., Stephan, D., Najmabadi, H., Smith, R. J. H., Bahlo, M. A novel splice site mutation in the RDX gene causes DFNB24 hearing loss in an Iranian family. (Letter) Am. J. Med. Genet. 149A: 555-558, 2009. [PubMed: 19215054] [Full Text: https://doi.org/10.1002/ajmg.a.32670]
Wilgenbus, K. K., Milatovich, A., Francke, U., Furthmayr, H. Molecular cloning, cDNA sequence, and chromosomal assignment of the human radixin gene and two dispersed pseudogenes. Genomics 16: 199-206, 1993. [PubMed: 8486357] [Full Text: https://doi.org/10.1006/geno.1993.1159]