Details

Autor(en) / Beteiligte

• Parzefall, Thomas
• Shivatzki, Shaked
• Lenz, Danielle R.
• Rathkolb, Birgit
• Ushakov, Kathy
• Karfunkel, Daphne
• Shapira, Yisgav
• Wolf, Michael
• Mohr, Manuela
• Wolf, Eckhard
• Sabrautzki, Sibylle
• de Angelis, Martin Hrabé
• Frydman, Moshe
• Brownstein, Zippora
• Avraham, Karen B.

Titel

Cytoplasmic Mislocalization of POU3F4 Due to Novel Mutations Leads to Deafness in Humans and Mice

Ist Teil von

• Human mutation, 2013-08, Vol.34 (8), p.1102-1110

Ort / Verlag

United States: Blackwell Publishing Ltd

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• ABSTRACT POU3F4 is a POU domain transcription factor that is required for hearing. In the ear, POU3F4 is essential for mesenchymal remodeling of the bony labyrinth and is the causative gene for DFNX2 human nonsyndromic deafness. Ear abnormalities underlie this form of deafness, characterized previously in multiple spontaneous, radiation‐induced and transgenic mouse mutants. Here, we report three novel mutations in the POU3F4 gene that result in profound hearing loss in both humans and mice. A p.Gln79* mutation was identified in a child from an Israeli family, revealed by massively parallel sequencing (MPS). This strategy demonstrates the strength of MPS for diagnosis with only one affected individual. A second mutation, p.Ile285Argfs*43, was identified by Sanger sequencing. A p.Cys300* mutation was found in an ENU‐induced mutant mouse, schwindel (sdl), by positional cloning. The mutation leads to a predicted truncated protein, similar to the human mutations, providing a relevant mouse model. The p.Ile285Argfs*43 and p.Cys300* mutations lead to a shift of Pou3f4 nuclear localization to the cytoplasm, demonstrated in cellular localization studies and in the inner ears of the mutant mice. The discovery of these mutations facilitates a deeper comprehension of the molecular basis of inner ear defects due to mutations in the POU3F4 transcription factor. DFNX2 (OMIM #304400) is the result of mutations in the POU3F4 (POU domain class 3, transcription factor 4, BRN‐4) transcription factor that belongs to subclass III of the POU superfamily. Targeted capture and massively parallel sequencing was used to detect a human POU4F3 mutation, demonstrating the strength of this approach for diagnosis with only one affected individual . A second human mutation leads to a frameshift and a replacement of the normal C‐terminal end of the protein with a new segment. A Pou3f4 mutation predicted to lead to a stop codon results in deafness in an ENU‐derived mutant mouse. The human and mouse mutations complement one another and help define the molecular mechanisms associated with POU3F4 hereditary hearing loss in humans.