Autosomal Recessive Nonsyndromic Hearing Impairment due to a Novel Deletion in the RDX Gene

Abstract

The RDX gene anchors cytoskeletal actin of stereocilia to hair cell transmembrane and is responsible for autosomal recessive nonsyndromic hearing impairment (ARNSHI) due to DFNB24. A genome scan was performed using DNA samples from a consanguineous Pakistani family with ARNSHI. A significant maximum two-point LOD score of 4.5 (θ = 0) and multipoint LOD score of 5.8 were achieved at marker D11S1998 (chr11 : 117.20 Mb). The region of homozygosity is bounded by markers D11S2000 (105.06 Mb) and D11S4464 (123.13 Mb) and contains the NSHI genes TECTA and RDX. Although no potentially causal variants were identified in the TECTA gene, within the RDX gene a novel deletion c.1076_1079delTTAA (p.Ile359Lysfs∗6) was identified. The RDX deletion segregates with ARNSHI within the family and was not observed in 500 control chromosomes. It is predicted to cause premature truncation of radixin at the α-helical domain and to result in nonfunctional transcripts within the cochlea. RDX isoforms which encode the coiled-coil region of the α-helical domain are deemed necessary for proper function of hair cell stereocilia.

CLIC5 stabilizes membrane‐actin filament linkages at the base of hair cell stereocilia in a molecular complex with radixin, taperin, and myosin VI

“…CLIC5 shares a compartment near the base of stereocilia [Gagnon et al, ] with RDX [Pataky et al, ], PTPRQ [Goodyear and Richardson, ; Sakaguchi et al, ], TPRN [Rehman et al, ], and MYO6 [Hasson et al, ; Sakaguchi et al, ]. Furthermore, deficiencies of MYO6 [Avraham et al, ; Melchionda et al, ; Ahmed et al, ; Mohiddin et al, ], RDX [Khan et al, ; Shearer et al, ; Lee et al, ], PTPRQ [Schraders et al, ; Shahin et al, ], TPRN [Li et al, ; Rehman et al, ], and CLIC5 [C. Zazo Seco, H. Kremer, M. Schraders, Radboud University Nijmegen Medical Centre, 2013, personal communication] are all linked to human deafness, underscoring the significance of this hypothetical protein complex.…”

“…With increased contrast, a faint band (arrowhead) corresponding to the 200 kDa migrating intact MYO6 band is detected in the CLIC5 eluate. Ahmed et al, 2003;Mohiddin et al, 2004], RDX [Khan et al, 2007;Shearer et al, 2009;Lee et al, 2011], PTPRQ [Schraders et al, 2010;Shahin et al, 2010], TPRN [Li et al, 2010;Rehman et al, 2010], and CLIC5 [C. Zazo Seco, H. Kremer, M. Schraders, Radboud University Nijmegen Medical Centre, 2013, personal communication] are all linked to human deafness, underscoring the significance of this hypothetical protein complex.…”

The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing

“…Perturbations of this molecular choreography underlie a number of severe hereditary hearing disorders, most commonly due to failure of either the mechanotransduction machinery itself, or corrupted stereociliar orientation, organization, or elongation . For example, the cause of human autosomal recessive hearing impairment DFNB24 is the genetic deletion of the ezrin–radixin–moesin (ERM) family protein, radixin (RDX)—a cross‐linker between plasma membranes and the stereociliar cytoskeleton. Radixin deficiency in mice leads to early postnatal hair bundle degeneration .…”

IceR improves proteome coverage and data completeness in global and single-cell proteomics

“…7h ). The latter is described to anchor cytoskeletal actin of stereocilia to hair cell membranes 40 . Interestingly, RDX showed the highest transcript and protein expression midway through the developmental trajectory (Fig.…”