Aldh inhibitor restores auditory function in a mouse model of human deafness

Autoři: Guang-Jie Zhu aff001;  Sihao Gong aff001;  Deng-Bin Ma aff001;  Tao Tao aff001;  Wei-Qi He aff001;  Linqing Zhang aff001;  Fang Wang aff001;  Xiao-Yun Qian aff001;  Han Zhou aff001;  Chi Fan aff001;  Pei Wang aff001;  Xin Chen aff001;  Wei Zhao aff001;  Jie Sun aff001;  Huaqun Chen aff003;  Ye Wang aff004;  Xiang Gao aff001;  Jian Zuo aff005;  Min-Sheng Zhu aff001;  Xia Gao aff001;  Guoqiang Wan aff001
Působiště autorů: Department of Otorhinolaryngology, Provincial Key Discipline of the affiliated Drum Tower Hospital of Nanjing University and Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, School of Medicine, Nanjing University, Nanj aff001;  Department of Otorhinolaryngology, Provincial Key Discipline of the affiliated Drum Tower Hospital of Nanjing University and Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, School of Medicine, Nanjing University, Nanj aff001;  Department of Otorhinolaryngology, Provincial Key Discipline of the affiliated Drum Tower Hospital of Nanjing University and Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, School of Medicine, Nanjing University, Nanj aff001;  Department of Otorhinolaryngology, Provincial Key Discipline of the affiliated Drum Tower Hospital of Nanjing University and Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, School of Medicine, Nanjing University, Nanj aff001;  Department of Otorhinolaryngology, Provincial Key Discipline of the affiliated Drum Tower Hospital of Nanjing University and Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, School of Medicine, Nanjing University, Nanj aff001;  Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda (CAM-SU) Genomic Resource Center, Medical College of Soochow University, Suzhou, China aff002;  College of Life Science, Nanjing Normal University, Nanjing, China aff003;  Nanjing MuCyte Biotechnology Co., Ltd., Nanjing, China aff004;  Department of Biomedical Sciences, School of Medicine, Creighton University, United States of America aff005;  Institute for Brain Sciences, Nanjing University, Nanjing, China aff006
Vyšlo v časopise: Aldh inhibitor restores auditory function in a mouse model of human deafness. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009040
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009040


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.

Klíčová slova:

Cochlea – Deafness – Genetically modified animals – Haploinsufficiency – Mouse models – Outer hair cells – Sensory perception – Signal inhibition


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