Revealing The Pathology And Molecular Basis Of DFNA15 Progressive Hearing Loss Via A Disease Mouse Model

POU4F3 mutation is associated with autosomal dominant deafness-15(DFNA 15),a common autosomal dominant form of progressive hearing loss.Similar to other genetic hearing disorders,DNFA15 deafness has no targeted drug or therapy so far.We here established a disease mouse model of DFNA15 progressive hearing loss with an identical mutation of Pou4f3 gene of the first reported case Israeli Jewish family H.With appreciation of this animal model,we firstly revealed the pathological alterations on cochlea and the molecular regulation of DFNA 15 deafness.We designed a target vector for making a knockin line with an 8 nucleotide deletion in the C-terminus of exon 2 and a new stop codon was created by reversing C to T and constructed mutant mice.The phenotypes of mice with three genotypings(Pou4f3△/+,Pou4f3△/+,Pou4f3+/+)were assessed by hearing function(auditory brainstem respons eand distortion product otoacoustic emission),behavioral analysis vestibular function,inner ear morphology.Also based on study of the animal model rou4f3△/+ mouse,the molecular pathologic characteristics and targeted therapeutic strategy of DFNA 15 was revealed.The Pou4f3△/+ mice displayed a progressive deafness in a similar manner of DFNA 15 patients.Histology analyses of the mutant Corti’s organ showed progressive spare inner hair cells with long and fused stereocilia.The out hair cells showed less stereocilia.Both inner and out hair cells had degenerative alterations including less mitochondrion and vacuole formation.Our result suggests that overexpressed Espin protein resulting from transcriptional disinhibition caused by Pou4f3 mutation may underlie the phenotypes of the cochlea.Moreover,inhibition of Espin expression by the retinoic acid antagonist 4-diethylaminobenzaldehyde(DEAB)suppressed the progression of hearing loss in the Pou4f3△/+ mice and cochlear Espin overexpression.Abnormal expression of Espin also might be regarded as a therapeutic target for the deafness.In addition,because the phenotypes of Pou4f3△/+ mice are highly consistent with DFNA15 patients,our results also provided with a strong gene-phenotype evidence of DFNA15 deafness,and an excellent disease model.