PMID- 35729109
OWN - NLM
STAT- MEDLINE
DCOM- 20220623
LR  - 20230119
IS  - 2041-4889 (Electronic)
VI  - 13
IP  - 6
DP  - 2022 Jun 21
TI  - Dnah9 mutant mice and organoid models recapitulate the clinical features of 
      patients with PCD and provide an excellent platform for drug screening.
PG  - 559
LID - 10.1038/s41419-022-05010-5 [doi]
LID - 559
AB  - 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.
CI  - (c) 2022. The Author(s).
FAU - Zheng, Rui
AU  - Zheng R
AD  - Department 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 University, Chengdu, China.
FAU - Yang, Wenhao
AU  - Yang W
AD  - Department of Pediatric Pulmonology and Immunology, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
AD  - Key Laboratory of Chronobiology (Sichuan University), National Health Commission 
      of China, Chengdu, China.
AD  - The 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 University, Chengdu, China.
AD  - Sichuan Birth Defects Clinical Research Center, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
FAU - Wen, Yuting
AU  - Wen Y
AD  - Department 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 University, Chengdu, China.
FAU - Xie, Liang
AU  - Xie L
AD  - Key Laboratory of Chronobiology (Sichuan University), National Health Commission 
      of China, Chengdu, China.
AD  - The 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 University, Chengdu, China.
AD  - Key Laboratory of Birth Defects and Related Diseases of Women and Children 
      (Sichuan University), Ministry of Education, Chengdu, China.
FAU - Shi, Fang
AU  - Shi F
AD  - The 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 University, Chengdu, China.
AD  - Key Laboratory of Birth Defects and Related Diseases of Women and Children 
      (Sichuan University), Ministry of Education, Chengdu, China.
FAU - Lu, Danli
AU  - Lu D
AD  - Department of Pediatric Pulmonology and Immunology, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
AD  - Key Laboratory of Chronobiology (Sichuan University), National Health Commission 
      of China, Chengdu, China.
AD  - The 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 University, Chengdu, China.
AD  - Sichuan Birth Defects Clinical Research Center, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
AD  - Key Laboratory of Birth Defects and Related Diseases of Women and Children 
      (Sichuan University), Ministry of Education, Chengdu, China.
FAU - Luo, Jiaxin
AU  - Luo J
AD  - Department of Pediatric Pulmonology and Immunology, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
AD  - Key Laboratory of Chronobiology (Sichuan University), National Health Commission 
      of China, Chengdu, China.
AD  - The 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 University, Chengdu, China.
AD  - Sichuan Birth Defects Clinical Research Center, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
AD  - Key Laboratory of Birth Defects and Related Diseases of Women and Children 
      (Sichuan University), Ministry of Education, Chengdu, China.
FAU - Li, Yan
AU  - Li Y
AD  - Department of Pediatric Pulmonology and Immunology, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
AD  - Key Laboratory of Chronobiology (Sichuan University), National Health Commission 
      of China, Chengdu, China.
AD  - The 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 University, Chengdu, China.
AD  - Sichuan Birth Defects Clinical Research Center, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
AD  - Key Laboratory of Birth Defects and Related Diseases of Women and Children 
      (Sichuan University), Ministry of Education, Chengdu, China.
FAU - Zhang, Rui
AU  - Zhang R
AD  - Department of Pediatric Pulmonology and Immunology, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
AD  - Key Laboratory of Chronobiology (Sichuan University), National Health Commission 
      of China, Chengdu, China.
AD  - The 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 University, Chengdu, China.
AD  - Sichuan Birth Defects Clinical Research Center, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
AD  - Key Laboratory of Birth Defects and Related Diseases of Women and Children 
      (Sichuan University), Ministry of Education, Chengdu, China.
FAU - Chen, Ting
AU  - Chen T
AD  - Department of Pediatric Pulmonology and Immunology, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
AD  - Key Laboratory of Chronobiology (Sichuan University), National Health Commission 
      of China, Chengdu, China.
AD  - The 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 University, Chengdu, China.
AD  - Sichuan Birth Defects Clinical Research Center, West China Second University 
      Hospital, Sichuan University, Chengdu, China.
AD  - Key Laboratory of Birth Defects and Related Diseases of Women and Children 
      (Sichuan University), Ministry of Education, Chengdu, China.
FAU - Chen, Lina
AU  - Chen L
AUID- ORCID: 0000-0001-9066-2099
AD  - Department of Pediatric Pulmonology and Immunology, West China Second University 
      Hospital, Sichuan University, Chengdu, China. chenlina_78@163.com.
AD  - Key Laboratory of Chronobiology (Sichuan University), National Health Commission 
      of China, Chengdu, China. chenlina_78@163.com.
AD  - The 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 University, Chengdu, China. 
      chenlina_78@163.com.
AD  - Sichuan Birth Defects Clinical Research Center, West China Second University 
      Hospital, Sichuan University, Chengdu, China. chenlina_78@163.com.
AD  - Key Laboratory of Birth Defects and Related Diseases of Women and Children 
      (Sichuan University), Ministry of Education, Chengdu, China. chenlina_78@163.com.
FAU - Xu, Wenming
AU  - Xu W
AUID- ORCID: 0000-0002-3686-229X
AD  - Department 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 University, Chengdu, China. xuwenming@scu.edu.cn.
FAU - Liu, Hanmin
AU  - Liu H
AUID- ORCID: 0000-0002-4633-911X
AD  - Department of Pediatric Pulmonology and Immunology, West China Second University 
      Hospital, Sichuan University, Chengdu, China. Liuhm@scu.edu.cn.
AD  - Key Laboratory of Chronobiology (Sichuan University), National Health Commission 
      of China, Chengdu, China. Liuhm@scu.edu.cn.
AD  - The 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 University, Chengdu, China. Liuhm@scu.edu.cn.
AD  - Sichuan Birth Defects Clinical Research Center, West China Second University 
      Hospital, Sichuan University, Chengdu, China. Liuhm@scu.edu.cn.
AD  - Key Laboratory of Birth Defects and Related Diseases of Women and Children 
      (Sichuan University), Ministry of Education, Chengdu, China. Liuhm@scu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220621
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - EC 3.6.4.2 (Axonemal Dyneins)
RN  - EC 3.6.4.2 (DNAH9 protein, human)
RN  - EC 3.6.4.2 (Dyneins)
SB  - IM
MH  - Animals
MH  - *Axonemal Dyneins/genetics/metabolism
MH  - Cilia/metabolism
MH  - Drug Evaluation, Preclinical
MH  - Dyneins/metabolism
MH  - *Dyskinesias/metabolism/pathology
MH  - Humans
MH  - *Kartagener Syndrome/genetics/metabolism/pathology
MH  - Mice
MH  - Mutation/genetics
MH  - Organoids/metabolism
PMC - PMC9210797
COIS- The authors declare no competing interests.
EDAT- 2022/06/22 06:00
MHDA- 2022/06/24 06:00
PMCR- 2022/06/21
CRDT- 2022/06/21 23:14
PHST- 2021/11/26 00:00 [received]
PHST- 2022/06/08 00:00 [accepted]
PHST- 2022/05/30 00:00 [revised]
PHST- 2022/06/21 23:14 [entrez]
PHST- 2022/06/22 06:00 [pubmed]
PHST- 2022/06/24 06:00 [medline]
PHST- 2022/06/21 00:00 [pmc-release]
AID - 10.1038/s41419-022-05010-5 [pii]
AID - 5010 [pii]
AID - 10.1038/s41419-022-05010-5 [doi]
PST - epublish
SO  - Cell Death Dis. 2022 Jun 21;13(6):559. doi: 10.1038/s41419-022-05010-5.