title: Cytoplasmic mislocalization of POU3F4 due to novel mutations leads to deafness in humans and mice.
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.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Thomas
authors.initials: T
authors.lastname: Parzefall
authors.forename: Shaked
authors.initials: S
authors.lastname: Shivatzki
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Lenz
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Kathy
authors.initials: K
authors.lastname: Ushakov
authors.forename: Daphne
authors.initials: D
authors.lastname: Karfunkel
authors.forename: Yisgav
authors.initials: Y
authors.lastname: Shapira
authors.forename: Michael
authors.initials: M
authors.lastname: Wolf
authors.forename: Manuela
authors.initials: M
authors.lastname: Mohr
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Sibylle
authors.initials: S
authors.lastname: Sabrautzki
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Moshe
authors.initials: M
authors.lastname: Frydman
authors.forename: Zippora
authors.initials: Z
authors.lastname: Brownstein
authors.forename: Karen B
authors.initials: KB
authors.lastname: Avraham
mesh_terms: D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism*; D003638:Deafness / Q000235:genetics* / Q000378:metabolism; D007758:Ear, Inner / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D050809:POU Domain Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; C091774:POU3F4 protein, human; C074067:Pou3f4 protein, mouse
keywords: DFNX2; ENU; cochlea; hearing loss