Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening
Abstract Primary cilia dyskinesia (PCD) is a rare genetic disease caused by ciliary structural or functional defects. It causes severe outcomes in patients, including recurrent upper and lower airway infections, progressive lung failure, and randomization of heterotaxy. To date, although 50 genes ha...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-06-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05010-5 |
| _version_ | 1811227207037616128 |
|---|---|
| author | Rui Zheng Wenhao Yang Yuting Wen Liang Xie Fang Shi Danli Lu Jiaxin Luo Yan Li Rui Zhang Ting Chen Lina Chen Wenming Xu Hanmin Liu |
| author_facet | Rui Zheng Wenhao Yang Yuting Wen Liang Xie Fang Shi Danli Lu Jiaxin Luo Yan Li Rui Zhang Ting Chen Lina Chen Wenming Xu Hanmin Liu |
| author_sort | Rui Zheng |
| collection | DOAJ |
| description | Abstract Primary cilia dyskinesia (PCD) is a rare genetic disease caused by ciliary structural or functional defects. It causes severe outcomes in patients, including recurrent upper and lower airway infections, progressive lung failure, and randomization of heterotaxy. To date, although 50 genes have been shown to be responsible for PCD, the etiology remains elusive. Meanwhile, owing to the lack of a model mimicking the pathogenesis that can be used as a drug screening platform, thereby slowing the development of related therapies. In the current study, we identified compound mutation of DNAH9 in a patient with PCD with the following clinical features: recurrent respiratory tract infections, low lung function, and ultrastructural defects of the outer dynein arms (ODAs). Bioinformatic analysis, structure simulation assay, and western blot analysis showed that the mutations affected the structure and expression of DNAH9 protein. Dnah9 knock-down (KD) mice recapitulated the patient phenotypes, including low lung function, mucin accumulation, and increased immune cell infiltration. Immunostaining, western blot, and co-immunoprecipitation analyses were performed to clarify that DNAH9 interacted with CCDC114/GAS8 and diminished their protein levels. Furthermore, we constructed an airway organoid of Dnah9 KD mice and discovered that it could mimic the key features of the PCD phenotypes. We then used organoid as a drug screening model to identify mitochondrial-targeting drugs that can partially elevate cilia beating in Dnah9 KD organoid. Collectively, our results demonstrated that Dnah9 KD mice and an organoid model can recapture the clinical features of patients with PCD and provide an excellent drug screening platform for human ciliopathies. |
| first_indexed | 2024-04-12T09:37:43Z |
| format | Article |
| id | doaj.art-2a3d95de1b7943fe9637fb598961c236 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T09:37:43Z |
| publishDate | 2022-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-2a3d95de1b7943fe9637fb598961c2362022-12-22T03:38:10ZengNature Publishing GroupCell Death and Disease2041-48892022-06-0113611410.1038/s41419-022-05010-5Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screeningRui Zheng0Wenhao Yang1Yuting Wen2Liang Xie3Fang Shi4Danli Lu5Jiaxin Luo6Yan Li7Rui Zhang8Ting Chen9Lina Chen10Wenming Xu11Hanmin Liu12Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan UniversityDepartment of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan UniversityDepartment of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan UniversityKey Laboratory of Chronobiology (Sichuan University), National Health Commission of ChinaThe Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan UniversityDepartment of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan UniversityDepartment of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan UniversityDepartment of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan UniversityDepartment of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan UniversityDepartment of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan UniversityDepartment of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan UniversityDepartment of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic, and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan UniversityDepartment of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan UniversityAbstract Primary cilia dyskinesia (PCD) is a rare genetic disease caused by ciliary structural or functional defects. It causes severe outcomes in patients, including recurrent upper and lower airway infections, progressive lung failure, and randomization of heterotaxy. To date, although 50 genes have been shown to be responsible for PCD, the etiology remains elusive. Meanwhile, owing to the lack of a model mimicking the pathogenesis that can be used as a drug screening platform, thereby slowing the development of related therapies. In the current study, we identified compound mutation of DNAH9 in a patient with PCD with the following clinical features: recurrent respiratory tract infections, low lung function, and ultrastructural defects of the outer dynein arms (ODAs). Bioinformatic analysis, structure simulation assay, and western blot analysis showed that the mutations affected the structure and expression of DNAH9 protein. Dnah9 knock-down (KD) mice recapitulated the patient phenotypes, including low lung function, mucin accumulation, and increased immune cell infiltration. Immunostaining, western blot, and co-immunoprecipitation analyses were performed to clarify that DNAH9 interacted with CCDC114/GAS8 and diminished their protein levels. Furthermore, we constructed an airway organoid of Dnah9 KD mice and discovered that it could mimic the key features of the PCD phenotypes. We then used organoid as a drug screening model to identify mitochondrial-targeting drugs that can partially elevate cilia beating in Dnah9 KD organoid. Collectively, our results demonstrated that Dnah9 KD mice and an organoid model can recapture the clinical features of patients with PCD and provide an excellent drug screening platform for human ciliopathies.https://doi.org/10.1038/s41419-022-05010-5 |
| spellingShingle | Rui Zheng Wenhao Yang Yuting Wen Liang Xie Fang Shi Danli Lu Jiaxin Luo Yan Li Rui Zhang Ting Chen Lina Chen Wenming Xu Hanmin Liu Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening Cell Death and Disease |
| title | Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening |
| title_full | Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening |
| title_fullStr | Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening |
| title_full_unstemmed | Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening |
| title_short | Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening |
| title_sort | dnah9 mutant mice and organoid models recapitulate the clinical features of patients with pcd and provide an excellent platform for drug screening |
| url | https://doi.org/10.1038/s41419-022-05010-5 |
| work_keys_str_mv | AT ruizheng dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT wenhaoyang dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT yutingwen dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT liangxie dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT fangshi dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT danlilu dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT jiaxinluo dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT yanli dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT ruizhang dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT tingchen dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT linachen dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT wenmingxu dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening AT hanminliu dnah9mutantmiceandorganoidmodelsrecapitulatetheclinicalfeaturesofpatientswithpcdandprovideanexcellentplatformfordrugscreening |