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Parzefall, T.* ; Shivatzki, S.* ; Lenz, D.R.* ; Rathkolb, B. ; Ushakov, K.* ; Karfunkel, D.* ; Shapira, Y.* ; Wolf, M.* ; Mohr, M.* ; Wolf, E.* ; Sabrautzki, S. ; Hrabě de Angelis, M. ; Frydman, M.* ; Brownstein, Z.* ; Avraham, K.B.*

Cytoplasmic mislocalization of POU3F4 due to novel mutations leads to deafness in humans and mice.

Hum. Mutat. 34, 1102-1110 (2013)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Hearing Loss ; Cochlea ; Enu ; Dfnx2; Sex-linked Deafness ; Hearing-loss ; Inner-ear ; Enu Mutagenesis ; Gene-expression ; Mouse Model ; Protein ; Dfn3 ; Localization ; Mesenchyme
ISSN (print) / ISBN 1059-7794
e-ISSN 1098-1004
Journal Human Mutation
Quellenangaben Volume: 34, Issue: 8, Pages: 1102-1110 Article Number: , Supplement: ,
Publisher Wiley
Reviewing status Peer reviewed