Cdh23 mutations in the mouse are associated with retinal dysfunction but not retinal degeneration
Introduction
Usher syndrome is characterized by hearing loss, retinitis pigmentosa, and, in some forms, vestibular dysfunction. Usher syndrome is estimated to have a frequency of 4·4/100 000 in the United States (Boughman et al., 1983), account for approximately half of the deaf–blind population and be responsible for approximately 18% of the cases of retinitis pigmentosa (Kimberling et al., 2000, Petit, 2001). There are three different sub-types of Usher syndrome with type 1 (USH1) being the most common and the most severe (Keats and Corey, 1999). Patients with USH1 are congenitally deaf, have vestibular dysfunction and generally develop retinitis pigmentosa in the first decade of life (Smith et al., 1994). Presently, there are at least seven genes involved in USH1 of which four have been identified. They encode myosin VIIa (Weil et al., 1995), harmonin (Bitner-Glindzicz et al., 2000, Verpy et al., 2000), protocadherin 15 (Ahmed et al., 2001, Alagramam et al., 2001) and cadherin 23 (Bolz et al., 2001, Bork et al., 2001). With the exception of myosin VIIa, little is known about the function of any of these molecules and particularly about their roles in retinal function. Given the prevalence of Usher syndrome in the population of people with retinitis pigmentosa, it is important to determine the function of these molecules in the retina and to establish experimental models for their investigation.
Cadherin 23 was recently shown to underlie both Usher syndrome type 1D (USH1D) (Bolz et al., 2001, Bork et al., 2001) and also non-syndromic deafness (DFNB12) (Bork et al., 2001) in humans, and deafness in the waltzer mouse (Di Palma et al., 2001). Cadherins are transmembrane proteins that are involved in calcium-dependent cell–cell adhesion. The extracellular domains of cadherins form homophilic interactions with molecules protruding from other membranes and the intracellular component binds to the actin cytoskeleton through a complex of other proteins. Cadherin 23 is known to be expressed in the mouse, monkey and human retinas (Bork et al., 2001, Di Palma et al., 2001, Siemens et al., 2002) and has been reported to be present in the developing retina (Siemens et al., 2002). To date, no precise expression pattern or function has been described for cadherin 23 in the adult retina; therefore, it is unclear why mutations in cadherin 23 cause retinitis pigmentosa.
There are at least 10 mutant alleles of Cdh23 (waltzer) in the mouse. Here we examined the retinas from mice homozygous for three of these alleles, all of which are thought to be null alleles (Di Palma et al., 2001, Wilson et al., 2001). Retinas were analyzed anatomically and with electroretinography (ERG) to determine whether the photoreceptors of Cdh23 mutant mice degenerate and/or display any functional abnormalities. Myosin VIIa, another molecule that can cause USH1 (Weil et al., 1995, Liu et al., 1998b), and cadherin 23 have been hypothesized to interact genetically in the ear (Lord and Gates, 1929, Deol, 1956, Boeda et al., 2002), though recently this result was not replicated in another study (Holme and Steel, 2002). Therefore, we analyzed a cross between Myo7a and Cdh23 mutant mice to test whether these molecules interact in the retina. This report is the first histological and functional analysis of retinas deficient in cadherin 23.
Section snippets
Animals
All animal procedures were conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and in accordance with the United Kingdom's Home Office regulations. Mice were bred in house and were maintained in relatively dim light, around 40 lux, on a 12 hr/12 hr light/dark cycle.
Cdh23 alleles. Three different recessive alleles of cadherin 23 (Cdh23) were used and each was on a different genetic background: Cdh23v, 75% CBA/Ca, 25% unknown heterogeneous
Cdh23 homozygous mutant retinas do not degenerate
Retinas of homozygous Cdh23 mutants were examined by histology to determine if there was any sign of retinal degeneration. Cdh23v mutants appeared normal at 1·5 and 4·0 months of age (data not shown and see below). Cdh23Alb and Cdh23v-2J mutants were examined at ages up to 12 months, and no sign of retinal degeneration was ever observed (Fig. 1). Moreover, unlike in mice mutant for Myo7a, the USH1B orthologue (Gibson et al., 1995, Weil et al., 1995), the melanosomes of the RPE were properly
Discussion
Recently, mutations in cadherin 23 (CDH23) have been shown to cause both non-syndromic deafness (DFNB12) (Bork et al., 2001) and USH1D (Bolz et al., 2001, Bork et al., 2001) in humans. USH1D is characterized by profound congenital deafness and early onset retinitis pigmentosa that often results in complete blindness. Cdh23 was also recently found to be mutated in the waltzer mouse (Di Palma et al., 2001). As a result of a developmental dysgenesis in hair cells of mutant mice (Di Palma et al.,
Acknowledgements
This work was supported by the MRC, EC(BMH4-CT96-132), and Defeating Deafness (K.P.S.) and NIH grant EY07042, NIH core grant EY12598, and a grant from the Foundation Fighting Blindness (D.S.W.).
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