Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D


Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss, vestibular dysfunction and visual impairment due to early onset retinitis pigmentosa1 (RP). So far, six loci (USH1AUSH1F) have been mapped, but only two USH1 genes have been identified: MYO7A (ref. 2) for USH1B and the gene encoding harmonin3,4 for USH1C. We identified a Cuban pedigree linked to the locus for Usher syndrome type 1D (MIM 601067) within the q2 region of chromosome 10 (ref. 5). Affected individuals present with congenital deafness and a highly variable degree of retinal degeneration. Using a positional candidate approach, we identified a new member of the cadherin gene superfamily, CDH23. It encodes a protein of 3,354 amino acids with a single transmembrane domain and 27 cadherin repeats. In the Cuban family, we detected two different mutations: a severe course of the retinal disease was observed in individuals homozygous for what is probably a truncating splice-site mutation (c.4488G→C), whereas mild RP is present in individuals carrying the homozygous missense mutation R1746Q. A variable expression of the retinal phenotype was seen in patients with a combination of both mutations. In addition, we identified two mutations, ΔM1281 and IVS51+5G→A, in a German USH1 patient. Our data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype. In an accompanying paper6, it is shown that mutations in the mouse ortholog cause disorganization of inner ear stereocilia and deafness in the waltzer mouse.

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Figure 1: Pedigree of a Cuban USH1D family.
Figure 2: CDH23 mutations in the Cuban USH1D family.
Figure 3: CDH23 mutations in a German USH1 patient.
Figure 4

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We thank B. Ressler and I. Jantke for technical assistance. This study was financially supported by Mrs. B. Höll, The Foundation Fighting Blindness, Faun-Stiftung, Forschung contra Blindheit, Initiative Usher-Syndrom, Deutsche Forschungsgemeinschaft, Pro Retina Deutschland and BONFOR.

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Correspondence to Andreas Gal.

Supplementary information

Table A

Detailed clinical data of patients from the USH Cuban family. Genotypes referring to the two mutations (R1746Q and c.4488G --> C) described in the paper are given for each individual. (PDF 19 kb)

Table B

95°C for 3 min; three cycles at 95°C for 15 s, AT+4°C for 10 s, 72°C for 30 s; three cycles at 95°C for 15 s, AT+2°C for 10 s, 72°C for 30 s; 30 cycles at 95°C for 15 s, AT for 10 s, 72°C for 30 s and 72°C for 10 min. (DOC 76 kb)

Table C

Non-synonymous sequence variants in the coding region of the human CDH23 gene. All substitutions were present in unaffected control individuals and are therefore unlikely to represent pathogenic mutations. (DOC 26 kb)

Figure A (PDF 23 kb)

Figure B

Characterization of the human CDH23 gene and protein. a, Complete amino acid sequence of the longest CDH23 isoform. Both microexons (exon 11 and exon 33) as well as exon 68 are alternatively spliced as shown by cDNA analysis. A putative signal peptide (1-23) and a single transmembrane domain (3067-3086) are marked by a dotted and a solid box, respectively. The 27 cadherin repeats are indicated by gray background. Positions of exons are indicated by arrows, exon numbering is given above the sequence. b, Phylogenetic tree (ClustalX, default parameters) of selected members of the cadherin superfamily based on the sequence of the first cadherin repeat. A calibration bar for the branch lengths is shown in the upper right corner. CDH23 is closely related to two Drosophila melanogaster proteins, CG6445 and CG3389, and to the human flamingo proteins. GenBank accession numbers of selected cadherins: E-cadherin (CAA84586), N-cadherin (AAB22854), VE-cadherin (AAB41796), CDH7 (BAA87415), Dachsous (AAA79329), Cdh3 (AAB50920), PCDH-alpha1 (AAD43699), PCDH-b2 (CAA60685), PCDH1 (AAA36419), PCDH7 (BAA25194), Flamingo1 (AAF61929), Flamingo2 (AAF61930), CDH23 (AF312024), CG6445 (AAF49351), CG3389 (AAF55082), Fat1 (CAA60685), MEGF1 (BAA32458). Ce, Caenorhabditis elegans; Dm, Drosophila; Hs, Homo sapiens; Rn, Rattus norvegicus. (PDF 15 kb)

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Bolz, H., von Brederlow, B., Ramírez, A. et al. Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat Genet 27, 108–112 (2001).

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