Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice

Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 ( DNAH10 ) encodes a subunit of the inner arm dynein...

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Veröffentlicht in:Frontiers of medicine 2023-10, Vol.17 (5), p.957-971
Hauptverfasser: Wang, Rongchun, Yang, Danhui, Tu, Chaofeng, Lei, Cheng, Ding, Shuizi, Guo, Ting, Wang, Lin, Liu, Ying, Lu, Chenyang, Yang, Binyi, Ouyang, Shi, Gong, Ke, Tan, Zhiping, Deng, Yun, Tan, Yueqiu, Qing, Jie, Luo, Hong
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container_issue 5
container_start_page 957
container_title Frontiers of medicine
container_volume 17
creator Wang, Rongchun
Yang, Danhui
Tu, Chaofeng
Lei, Cheng
Ding, Shuizi
Guo, Ting
Wang, Lin
Liu, Ying
Lu, Chenyang
Yang, Binyi
Ouyang, Shi
Gong, Ke
Tan, Zhiping
Deng, Yun
Tan, Yueqiu
Qing, Jie
Luo, Hong
description Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 ( DNAH10 ) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10 -knockin mice harboring missense variants and Dnah10 -knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.
doi_str_mv 10.1007/s11684-023-0988-8
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Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 ( DNAH10 ) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C &gt; T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10 -knockin mice harboring missense variants and Dnah10 -knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.</description><identifier>ISSN: 2095-0217</identifier><identifier>EISSN: 2095-0225</identifier><identifier>DOI: 10.1007/s11684-023-0988-8</identifier><identifier>PMID: 37314648</identifier><language>eng</language><publisher>Beijing: Higher Education Press</publisher><subject>Animals ; Cilia - genetics ; Cilia - metabolism ; Ciliary Motility Disorders - genetics ; Dyneins - genetics ; Dyneins - metabolism ; Dyskinesia ; Humans ; Male ; Medicine ; Medicine &amp; Public Health ; Mice ; Mutation ; Research Article ; Semen - metabolism ; Sperm</subject><ispartof>Frontiers of medicine, 2023-10, Vol.17 (5), p.957-971</ispartof><rights>Higher Education Press 2023</rights><rights>2023. 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Med</addtitle><addtitle>Front Med</addtitle><description>Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 ( DNAH10 ) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C &gt; T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10 -knockin mice harboring missense variants and Dnah10 -knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. 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source MEDLINE; SpringerLink Journals - AutoHoldings
subjects Animals
Cilia - genetics
Cilia - metabolism
Ciliary Motility Disorders - genetics
Dyneins - genetics
Dyneins - metabolism
Dyskinesia
Humans
Male
Medicine
Medicine & Public Health
Mice
Mutation
Research Article
Semen - metabolism
Sperm
title Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice
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