December 2002
Volume 43, Issue 13
ARVO Annual Meeting Abstract  |   December 2002
Identification and In Vitro Expression of Novel CDH23 Mutations of Patients With Usher Syndrome Type 1D
Author Affiliations & Notes
  • A Gal
    Institute Human Genetics University Hosp Eppendorf Hamburg Germany
  • B von Brederlow
    Institute Human Genetics University Hosp Eppendorf Hamburg Germany
  • G Rudolph
    Dept Ophthalmology LMU Klinikum Innenstadt München Germany
  • B Lorenz
    Abt Paed Ophthalmol Univ Eye Hosp Regensburg Germany
  • H Bolz
    Institute Human Genetics University Hosp Eppendorf Hamburg Germany
  • Footnotes
    Commercial Relationships   A. Gal, None; B. von Brederlow, None; G. Rudolph, None; B. Lorenz, None; H. Bolz, None. Grant Identification: Support: Grants of FFB, FAUN-Stiftung, and BMBF
Investigative Ophthalmology & Visual Science December 2002, Vol.43, 797. doi:
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      A Gal, B von Brederlow, G Rudolph, B Lorenz, H Bolz; Identification and In Vitro Expression of Novel CDH23 Mutations of Patients With Usher Syndrome Type 1D . Invest. Ophthalmol. Vis. Sci. 2002;43(13):797.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract: : Purpose: To perform mutation screening of the CDH23 gene in patients with classical phenotype of Usher syndrome type 1D (USH1D), previously excluded for USH1B and USH1C. Usher syndrome designates a group of clinically and genetically heterogeneous disorders with congential or early-onset sensorineural hearing loss and progressive retinitis pigmentosa (RP). USH type 1, with additional vestibular dysfunction, represents the most severe form. It was recently shown that mutations in CDH23, encoding cadherin-23, underlie USH1D. CDH23 is a cell adhesion molecule of 3,354 amino acids, with a single transmembrane domain and 27 extracellular cadherin repeats (EC), each containing conserved motifs required for Ca2+-binding. Methods: Amplicons of the 69 CDH23 exons were screened by SSCP. In vitro analysis of putative splice site mutations was performed by the GibcoBRL «Exon Trapping System’. Results: On 8 disease alleles of 4 patients, 4 different mutations were identified, 3 of them novel (c.6933delT, c.5712G≷A, and IVS45-9G≷A). None of the mutations detected in these patients were present on 100 control chromosomes. In the case of the apparently synonymous mutation c.5712G≷A (G112), the last base of exon 42 is affected that is G in 80% of cases (compared to A in only 8% of exons). The mutant sequence was not recognized as a splice site in computer-assisted analysis. Exon trapping showed skipping of exon 42. The corresponding predicted protein lacks a small portion of EC17 and almost half of EC18. The IVS45-9G≷A mutation created a novel acceptor splice site motif (AGGT) 9 bp upstream the 5’-end of exon 46, and the insertion of 7 intronic bp was observed in exon trapping experiments. Due to the frameshift, a truncated protein of 2029 amino acids including 12 residues unrelated to CDH23 is predicted. Both IVS45-9G≷A, and the previously reported IVS51+5G≷A mutation, were each found in more than one patient. Haplotype analysis using 9 SNPs within CDH23 suggests a common ancestoral origin for each of the mutations. Among the total of 52 USH1 cases studied by us, CDH23 mutations account for 10% of all disease alleles, which is lower than previously predicted. Conclusion: In patients with a typical USH1D phenotype, it seems that most of the CDH23 mutations result in loss of function of the protein due to truncation or loss of numerous amino acids, with a high frequency of mutations (6/17, accounting for 58% of all disease alleles reported so far) resulting in impaired splicing.

Keywords: 480 mutations • 562 retinal degenerations: hereditary • 420 genetics 

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