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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 39/3/195    most recent 00100.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lee, H. K. Articles by Kim, U.-K. PubMed PubMed Citation Articles by Lee, H. K. Articles by Kim, U.-K.

Research Articles

Clinical and molecular characterizations of novel POU3F4 mutations reveal that DFN3 is due to null function of POU3F4 protein

¹Department of Biology, Kyungpook National University, Daegu;
²Department of Otorhinolaryngology, Kwandong University College of Medicine, Goyang;
³Department of Anatomy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul;
⁴Department of Immunology, Keimyung University School of Medicine;
⁵Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Kyungpook National University, Daegu, South Korea;
⁶Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;
⁷Department of Otorhinolaryngology, Yonsei University College of Medicine; and
⁸Soree Ear Clinic, Seoul, South Korea

X-linked deafness type 3 (DFN3), the most prevalent X-linked form of hereditary deafness, is caused by mutations in the POU3F4 locus, which encodes a member of the POU family of transcription factors. Despite numerous reports on clinical evaluations and genetic analyses describing novel POU3F4 mutations, little is known about how such mutations affect normal functions of the POU3F4 protein and cause inner ear malformations and deafness. Here we describe three novel mutations of the POU3F4 gene and their clinical characterizations in three Korean families carrying deafness segregating at the DFN3 locus. The three mutations cause a substitution (p.Arg329Pro) or a deletion (p.Ser310del) of highly conserved amino acid residues in the POU homeodomain or a truncation that eliminates both DNA-binding domains (p.Ala116fs). In an attempt to better understand the molecular mechanisms underlying their inner ear defects, we examined the behavior of the normal and mutant forms of the POU3F4 protein in C3H/10T1/2 mesodermal cells. Protein modeling as well as in vitro assays demonstrated that these mutations are detrimental to the tertiary structure of the POU3F4 protein and severely affect its ability to bind DNA. All three mutated POU3F4 proteins failed to transactivate expression of a reporter gene. In addition, all three failed to inhibit the transcriptional activity of wild-type proteins when both wild-type and mutant proteins were coexpressed. Since most of the mutations reported for DFN3 thus far are associated with regions that encode the DNA binding domains of POU3F4, our results strongly suggest that the deafness in DFN3 patients is largely due to the null function of POU3F4.

hearing loss; X-linked deafness type 3; inner ear