POU4F3 in deafness and treatment - the POU4F3 gene encodes a transcription factor that is essential for sensory hair cell differentiation, survival, and regeneration

The National Institute on Deafness and Other Communication Disorders, a component of the Department of Health and Human Services National Institutes of Health, awarded Creighton University $350,000 on July 15, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) for Project Grant R01DC022260.

The award funds investigation of POU4F3, a transcription factor essential for sensory hair cell differentiation, survival, and regeneration. Mutations in POU4F3 cause autosomal dominant hearing loss (DFNA15), estimated to account for 2.5 percent of autosomal dominant hearing loss cases. Using animal models, the research will characterize POU4F3 distal enhancers and their inactivation during hair cell maturation; reveal molecular mechanisms underlying POU4F3 haploinsufficiency-induced hearing loss; and test efficacy of strategies for delivering and regulating exogenous POU4F3 gene to compensate for mutant alleles and preserve hearing.

Work is performed in Omaha, Nebraska. The period of performance extends through June 30, 2030.

Mutations in POU4F3 lead to hearing loss in patients (DFNA15), which is estimated to account for 2.5% of autosomal dominant hearing loss cases. POU4F3 haploinsufficiency has been identified as the cause of hearing loss in DFNA15 patients, but there remain unanswered questions as to why DFNA15 patients experience early onset hearing loss yet have good hearing in their early childhood, how POU4F3 haploinsufficiency leads to hair cell death and hearing loss, and whether increased expression of POU4F3 in hair cells is therapeutically beneficial to DFNA15 patients. In this project, using animal models, we will test our central hypothesis that during normal hair cell maturation, transcription of POU4F3 (mouse ortholog of human POU4F3 gene) is down-regulated due to the inactivation of distal enhancers, leading to the reduction of POU4F3 protein; and pathogenic mutations in one POU4F3 allele further exacerbated POU4F3 reduction to a level insufficient to maintain the expression of POU4F3 target genes, such as stereocilia genes, resulting in hair cell dysfunction and hearing loss. We also expect that hair cell specific POU4F3 expression from an exogenous gene will be able compensate for the mutant POU4F3 allele, maintain the expression of POU4F3 target genes, prevent hair cell death and preserve hearing. Specifically, we plan to characterize POU4F3 distal enhancers and investigate whether inactivation of these distal enhancer leads to transcriptional down-regulation of POU4F3 gene during hair cell maturation (aim 1); to reveal the molecular mechanisms underlying POU4F3 haploinsufficiency-induced hearing loss (aim 2); and to test the efficacy of multiple strategies for delivering and regulating the exogenous POU4F3 gene (aim 3). This project will help US gain a better understanding of DFNA15 pathogenesis, improve DFNA15 diagnostic accuracy, and develop effective treatments for DFNA15.