Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice
Rongchun Wang1,2,3, Danhui Yang1,2,3, Chaofeng Tu4,5, Cheng Lei1,2,3, Shuizi Ding1,2,3, Ting Guo1,2,3, Lin Wang1,2,3, Ying Liu1,2,3, Chenyang Lu1,2,3, Binyi Yang1,2,3, Shi Ouyang6, Ke Gong7, Zhiping Tan8, Yun Deng6, Yueqiu Tan4,5, Jie Qing1,2,3(), Hong Luo1,2,3()
1. Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, China 2. Research Unit of Respiratory Disease, Central South University, Changsha 410011, China 3. Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha 410011, China 4. Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha 410078, China 5. Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410078, China 6. Zebrafish Genetics Laboratory, College of Life Sciences, Hunan Normal University, Changsha 410081, China 7. Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Central South University, Changsha 410011, China 8. Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, China
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.
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