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A novel D458V mutation in the SANS PDZ binding motif causes atypical Usher syndrome

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Abstract

Homozygosity mapping and linkage analysis in a Turkish family with autosomal recessive prelingual sensorineural hearing loss revealed a 15-cM critical region at 17q25.1–25.3 flanked by the polymorphic markers D17S1807 and D17S1806. The maximum two-point lod score was 4.07 at θ=0.0 for the marker D17S801. The linkage interval contains the Usher syndrome 1G gene (USH1G) that is mutated in patients with Usher syndrome (USH) type 1g and encodes the SANS protein. Mutation analysis of USH1G led to the identification of a homozygous missense mutation D458V at the −3 position of the PDZ binding motif of SANS. This mutation was also present homozygously in one out of 64 additional families from Turkey with autosomal recessive nonsyndromic hearing loss and heterozygously in one out of 498 control chromosomes. By molecular modeling, we provide evidence that this mutation impairs the interaction of SANS with harmonin. Ophthalmologic examination and vestibular evaluation of patients from both families revealed mild retinitis pigmentosa and normal vestibular function. These results suggest that these patients suffer from atypical USH.

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Acknowledgements

We are grateful to the members of the families for participating in this study. The authors thank E. Kandemir, E. Sözen for technical assistance, and C. Hoyng for valuable discussion. This study was supported by the Karadeniz Technical University Research Fund (project no. 2002.114.001.3), the Heinsius Houbolt Foundation, Stichting Irene Kinderziekenhuis, and Stichting Vrienden van Effatha.

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Authors and Affiliations

  1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    E. Kalay, A. P. M. de Brouwer, J. G. A. M. Heister, F. P. M. Cremers & H. G. Brunner

  2. Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    E. Kalay, A. P. M. de Brouwer, C. W. R. J. Cremers & H. Kremer

  3. Department of Medical Biology and Genetics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey

    E. Kalay & A. Karaguzel

  4. Department of Otorhinolaryngology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey

    R. Caylan

  5. Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen, Nijmegen, The Netherlands

    S. B. Nabuurs

  6. Center for Molecular Medicine Cologne (CMMC) and Institute of Human Genetics, University of Cologne, Cologne, Germany

    B. Wollnik

  7. Department of Ophthalmology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey

    H. Erdol

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  1. E. Kalay
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  2. A. P. M. de Brouwer
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  9. F. P. M. Cremers
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  10. C. W. R. J. Cremers
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Correspondence to E. Kalay.

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E. Kalay and A.P.M. de Brouwer contributed equally to this work

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Kalay, E., de Brouwer, A.P.M., Caylan, R. et al. A novel D458V mutation in the SANS PDZ binding motif causes atypical Usher syndrome. J Mol Med 83, 1025–1032 (2005). https://doi.org/10.1007/s00109-005-0719-4

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