F. Di Palma et al., Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D, NAT GENET, 27(1), 2001, pp. 103-107
Mouse chromosome 10 harbors several loci associated with hearing loss, incl
uding waltzer (v), modifier-of deaf waddler (mdfw) and Age-related hearing
loss(1) (Ahl). The human region that is orthologous to the mouse 'waltzer'
region is located at 10q21-q22 and contains the human deafness loci DFNB12
and USH1D (refs. 2,3). Numerous mutations at the waltzer locus have been do
cumented causing erratic circling and hearing loss(4-7). Here we report the
identification of a new gene mutated in v. The 10.5-kb Cdh23 cDNA encodes
a very large, single-pass transmembrane protein, that we have called otocad
herin. It has an extracellular domain that contains 27 repeats; these show
significant homology to the cadherin ectodomain. In v(6J), a GT transversio
n creates a premature stop codon. In v(Alb), a Cr exchange generates an ect
opic donor splice site, effecting deletion of 119 nucleotides of exonic seq
uence. In v(2J), a GA transition abolishes the donor splice site, leading t
o aberrant splice forms. All three alleles are predicted to cause loss of f
unction. We demonstrate Cdh23 expression in the neurosensory epithelium and
show that during early hair-cell differentiation, stereocilia organization
is disrupted in v(2J) homozygotes. Our data indicate that otocadherin is a
critical component of hair bundle formation. Mutations in human CDH23 caus
e Usher syndrome type 1D and thus, establish waltzer as the mouse model for
USH1D.