Open AccessAldh inhibitor restores auditory function in a mouse model of human deafness
Author(s) -
Guanghao Zhu,
Sihao Gong,
Dengbin Ma,
Tao Tao,
Wei–Qi He,
Linqing Zhang,
Fang Wang,
Xiaoyun Qian,
Han Zhou,
Fan Cheng,
Pei Wang,
Xin Chen,
Wei Zhao,
Jie Sun,
Huaqun Chen,
Ye Wang,
Xiang Gao,
Jian Zuo,
Min–Sheng Zhu,
Xia Gao,
Guoqiang Wan
Publication year - 2020
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1009040
Subject(s) - haploinsufficiency , biology , hair cell , retinoic acid , hearing loss , aldehyde dehydrogenase , mutant , malondialdehyde , organ of corti , genetics , mutation , cochlea , biochemistry , microbiology and biotechnology , gene , audiology , phenotype , neuroscience , medicine , oxidative stress
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.