Mouse Models That Lack Pendrin Expression

The first mouse model, Slc26a4^AIA (formerly called Slc26a4~^l~ or Pds^-1-), is a knockout mouse maintained in the 129S6 strain, in which exon 8 of Slc26a4 is replaced with a neomycin cassette (Everett et al. 2001). The replacement introduces a frame shift, which prevents the generation of a functional protein. Slc26a4^AA mice develop an enlarged vestibular aqueduct and a Mondini-like dysplasia of the cochlea, fail to develop hearing and display vestibular deficits. The hearing and balance phenotype of Slc26a4^AIA mice is more severe than the phenotype in most patients with DFNB4 or Pendred syndrome, who, in many cases, are born with residual hearing that often deteriorates within the first 3 years (Kim et al. 2015).

Consistent with the recessive inheritance pattern, Slc26a4^A/+ mice develop normal sensory systems and normal hearing and balance. Slc26a4^AA and Slc26a4^A/+ mice have been used extensively to investigate the consequence of a complete lack of pendrin for the development of the inner ear. Further, Slc26a4^AIA and Slc26a4^A/+ mice have been used as background for transgenic mouse models that feature temporally or spatially limited pendrin expression from a transgene (Choi et al. 2011, Li et al. 2013a).

Several of the phenotypic features of Slc26a4^AIA mice have been observed in the

pendrin-mutation knock-in mouse, Slc26a4^{Tm1DontuhITm1Dontuh}. Slc26a4^{Tm1DontuhITm1Dontuh}

mice, which are maintained in the C57BLI6 strain, contain a splice-site mutation at exon 8 of Slc26a4. This mutation introduces a frame shift and a new stop-codon designed to recapitulate the human mutation c.919-2A > G, which is the most prevalent mutation in China, Taiwan, and Mongolia (Lu et al. 2011; Tsukada et al. 2015). Similar to Slc26a4^MA mice, Slc26a4^{Tm1DontuhITm1Dontuh} mice lack exon 8 of Slc26a4, which leads to a similar phenotype.

The phenotypes of Slc26a4^AA and sic26a4^{TmlDoMummlDoMub} mice bear a clear resemblance to the human phenotype. In contrast, sic26a4^{Tm2Dontuh/Tm2Dontuh} mice, also maintained in the C57BL/6 strain, contain a single-nucleotide mutation designed to recapitulate the human mutation p. H723R, which is the most prevalent mutation in Japan and Korea (Lu et al. 2013; Tsukada et al. 2015). Slc26a4^{Tm2Dontuh/ Tm2Dontuh} mice, however, have normal hearing and balance (Lu et al. 2013). The basis for this latter observation is unknown, but illustrates the challenges in developing mouse models that closely approximate the human EVA phenotype.