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. 2001 Jan;68(1):26-37.
doi: 10.1086/316954. Epub 2000 Nov 21.

Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23

J M Bork  1 , L M Peters, S Riazuddin, S L Bernstein, Z M Ahmed, S L Ness, R Polomeno, A Ramesh, M Schloss, C R Srisailpathy, S Wayne, S Bellman, D Desmukh, Z Ahmed, S N Khan, V M Kaloustian, X C Li, A Lalwani, S Riazuddin, M Bitner-Glindzicz, W E Nance, X Z Liu, G Wistow, R J Smith, A J Griffith, E R Wilcox, T B Friedman, R J Morell
Affiliations

Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23

J M Bork et al. Am J Hum Genet. 2001 Jan.

Abstract

Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seven highly consanguineous families segregating nonsyndromic autosomal recessive deafness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D10S1737, approximately 0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in families with USH1D. Six missense mutations were found in five families with DFNB12, and two nonsense and two frameshift mutations were found in four families with USH1D. A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina. CDH23 is also expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA.

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Figures

Figure 1
Figure 1
Pedigrees of five consanguineous families with DFNB12 and of three families with USH1D, segregating mutant alleles of CDH23. The pedigree for family 304, who are affected by USH1D, has been published elsewhere (Wayne et al. 1996). Blackened symbols represent individuals with clinically documented congenital deafness, retinal degeneration, and vestibular dysfunction, as described in the key. Genotype and haplotype data for family PKSR46a are shown. For the DFNB12 locus, the haplotype of unaffected individual 27 demonstrates the proximal breakpoint, at D10S1694, and that of affected individual 29 demonstrates the distal breakpoint, at D10S1737. 152N13aat is a polymorphic trinucleotide repeat identified on BAC 152N13.
Figure 2
Figure 2
Genetic and physical map of the DFNB12 locus defined by proximal and distal breakpoints in family PKSR46a. The Center for Medical Genetics, Marshfield Medical Research Foundation map distance of polymorphic markers is shown on the left. The proximal breakpoint, marker D10S1694, and the distal breakpoint, marker D10S1737, are shown as crosses on the chromosome, and the linked markers are shown as blackened circles on the chromosome. Both the BACs spanning the linked region and the 18 candidate genes that were sequenced for mutations are shown. Locus designations are italicized. Nonitalicized entries represent either clones that have no associated locus designation or novel genes that have significant homology to other genes. There are two gaps in the BAC contig, and 150D20 is the only BAC in the region with a finished sequence.
Figure 3
Figure 3
CDH23 cDNAs and the structure of the cadherin-23 protein (GenBank accession number AY010111). Mutations described in the text are indicated below the protein structure, and the +1G→A donor–splice-site mutations are indicated above the structure, by arrows. Intron 15 of CDH23 contains a nested gene (FLJ00041 [GenBank accession number AK024449]) encoded on the opposite strand. BLAST analysis reveals that the probable mouse orthologues of CDH23 and FLJ00041 are encoded on BAC RP23-161B11. EC denotes the extracellular cadherin repeat, and TM denotes a transmembrane spanning region, as predicted by TMpred.
Figure 4
Figure 4
Northern blot analysis. Lanes 1–6 contain 10 μg each of total RNA from retina, ciliary body, retinal pigmented epithelium-choroid, lens, iris, and brain. Positions of bands from a 9.5–0.24-kb RNA ladder are indicated along the right margin. Shown is a 4-d exposure to autoradiograph film. The 9.5-kb band for human retina is possibly a doublet. A 1-wk exposure to a PhosphoImager screen shows identical results, with the presence of no additional bands (data not shown).
Figure 5
Figure 5
Nucleotide sequence of mutations in representative families with USH1D and DFNB12, with wild-type sequence shown below the mutant allele. The nucleotide and protein sequences of CDH23 and cadherin-23 are based on data for GenBank accession number AY010111. Arrows indicate the altered nucleotide of the mutant CDH23 allele. A, Mutation of conserved donor splice site in family 304, with USH1D (Wayne et al. 1996). The canonical GT donor dinucleotides are underlined, and the splice site is indicated by an arrowhead. B, Nonsense mutation in family PKZA56, with USH1D leading to premature termination of translation. C, Missense mutation in family PKSR46a, with DFNB12, with aspartic acid replaced by an asparagine.
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References

Electronic-Database Information

    1. BLAST-CD, http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi
    1. Center for Medical Genetics, Marshfield Medical Research Foundation, http://research.marshfieldclinic.org/genetics/
    1. GenBank Overview, http://www.ncbi.nlm.nih.gov/Genbank/GenbankOverview.html
    1. GeneMachine, Division of Intramural Research, http://genome.nhgri.nih.gov/genemachine/
    1. Hereditary Hearing Loss Homepage, http://www.uia.ac.be/dnalab/hhh/ (for markers flanking known DFNB loci)

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