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Molecular and Cellular Biology, November 2003, p. 7957-7964, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.7957-7964.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The DFNA15 Deafness Mutation Affects POU4F3 Protein Stability, Localization, and Transcriptional Activity

Sigal Weiss,1 Irit Gottfried,1 Itay Mayrose,1 Suvarna L. Khare,2 Mengqing Xiang,2 Sally J. Dawson,3 and Karen B. Avraham1*

Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel,1 Center for Advanced Biotechnology and Medicine,2 Department of Pediatrics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey,3 Department of Immunology and Molecular Pathology, University College London Medical School, London, United Kingdom4

Received 2 May 2003/ Returned for modification 16 June 2003/ Accepted 12 August 2003

A mutation in the POU4F3 gene (BRN-3.1, BRN3C) is responsible for DFNA15 (MIM 602459), autosomal-dominant nonsyndromic hearing loss. POU4F3 is a member of the POU family of transcription factors and is essential for inner-ear hair cell maintenance. To test the potential effects of the human POU4F3 mutation, we performed a series of experiments in cell culture to mimic the human mutation. Mutant POU4F3 loses most of its transcriptional activity and most of its ability to bind to DNA and does not function in a dominant-negative manner. Moreover, whereas wild-type POU4F3 is found exclusively in the nucleus, our studies demonstrate that the mutant protein is localized both to the nucleus and the cytoplasm. Two nuclear localization signals were identified; both are essential for proper nuclear entry of POU4F3 protein. We found that the mutant protein half-life is longer than that of the wild type. We propose that the combination of defects caused by the mutation on the function of the POU4F3 transcription factor eventually leads to hair cell morbidity in affected family H members.

* Corresponding author. Mailing address: Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Phone: 972-3-6407030. Fax: 972-3-6409360. E-mail: karena{at}post.tau.ac.il.

Molecular and Cellular Biology, November 2003, p. 7957-7964, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.7957-7964.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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