Abstract
Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with a Pou4f3 gene mutation (Pou4f3Δ) identical to that found in a familial case of DFNA15. The Pou4f3(Δ/+) mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in the Pou4f3(Δ/+) cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of the Pou4f3(Δ/+) mice was significantly modified by other genetic and environmental factors. Using Pou4f3(-/+) heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of the Pou4f3 gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstrate Pou4f3 haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss.
Highlights
Hearing loss is one of the most common sensory defects resulting from both genetic and environmental insults that affect more than 250 million people worldwide [1]
We established a novel mouse model with the exact Pou4f3 mutation identified in human patients
We established a knock-in mouse line with an 8bp deletion and a C to T (C-T) reversion of the mouse Pou4f3 gene (Pou4f3Δ; S1A and S1B Fig), which was identical to the POU4F3 mutation found in an Israeli Jewish DFNA15 patient family [3]
Summary
Hearing loss is one of the most common sensory defects resulting from both genetic and environmental insults that affect more than 250 million people worldwide [1]. Despite the prevalence of hearing loss, no Food and Drug Administration-approved therapeutic treatment is currently available. Among the genetic hearing disorders, 20% of the cases are the autosomal dominant inheritance of nonsyndromic hearing loss [2]. POU4F3 mutations are associated with DFNA15, one of the common autosomal dominant forms of progressive hearing loss [3,4,5]. Studies using the Pou4f3-null mice indicate that Pou4f3 plays an essential role in differentiation and survival of inner ear hair cells [6,7,8]. How Pou4f3 mutations in human patients cause the dominant form of progressive hearing loss remains unknown
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