Article

Identification and in vitro expression of novel CDH23 mutations of patients with Usher syndrome type 1D

Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Human Mutation (Impact Factor: 5.05). 03/2002; 19(3):268-73. DOI: 10.1002/humu.10049
Source: PubMed

ABSTRACT Usher syndrome (USH) is a group of autosomal recessive sensory disorders characterized by progressive retinitis pigmentosa (RP) and sensorineural hearing impairment. Usher syndrome type 1 (USH1), with additional vestibular dysfunction, represents the most severe form and shows extensive allelic and non-allelic heterogeneity. At least six USH1 loci exist (USH1A-F), and four of the underlying genes have been identified. Recently, a novel gene, cadherin 23 (CDH23), was shown to be mutated in USH1D. We performed mutation screening by single strand conformation polymorphism (SSCP) analysis and direct sequencing on 33 USH1 patients previously excluded for USH1B and USH1C. On eight disease alleles of four patients, four different mutations were identified, three of them novel (c.6933delT, c.5712G-->A, and IVS45-9G-->A). Exon trapping experiments were performed with two mutations. In the case of a c.5712G-->A transition of the last base of exon 42, that is an apparently synonymous mutation, skipping of exon 42 was observed. By the mutation IVS45-9G-->A, a novel splice acceptor site was created and the insertion of 7 intronic bp was observed. Two mutations, IVS45-9G-->A and the previously described IVS51+5G-->A, were each found in more than one patient. Haplotype analysis by SNPs within CDH23 suggests common ancestors for each of the mutations. Among the total of 52 USH1 cases studied by us, CDH23 mutations account for about 10% of all disease alleles. Our results further suggest that in patients with a typical USH1D phenotype, a significant portion of CDH23 mutations leads to premature termination of translation or loss of numerous amino acid residues, with a high frequency of changes causing aberrant splicing of CDH23 mRNA.

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    • "Eight pathogenic or presumably pathogenic mutations in CDH23 were found in six patients, specifically, a previously reported mutation that affects splicing (c.6050-9G>A) [54], a novel nucleotide deletion (c.6404_6405delAG; p.E2135fsX31), and six missense mutations [55,56], four of which (p.R1189W, p.R1379P, p.D2639G, and p.R3043W) had not been previously reported. They affect amino acid residues located in the 11th, 13th and 25th cadherin repeat and the extracellular region adjacent to the transmembrane domain (3065-3085), respectively (Tables 2, 3 Figure 1). "
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    • "a Mutation lies within linker region between these two EC-repeat domains. b Mutations reported by either Bolz et al. (2001) or von Brederlow (2002). c Detected at either beginning or end of the exon, predicted to decrease splicing efficiency. "
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