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

作　　者：Rongchun Wang Danhui Yang Chaofeng Tu Cheng Lei Shuizi Ding Ting Guo Lin Wang Ying Liu Chenyang Lu Binyi Yang Shi Ouyang Ke Gong Zhiping Tan Yun Deng Yueqiu Tan Jie Qing Hong Luo 

机构地区：[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

出　　处：《Frontiers of Medicine》2023年第5期957-971,共15页医学前沿（英文版）

基　　金：supported by the National Natural Science Foundation of China (Nos.82070003,82100057,81900002,82101961,31970504,and 31772548);Natural Science Foundation of Hunan Province,China (Nos.2020JJ5805 and 2021JJ30943);Xiangya Clinical Big Data System Construction Project in Pulmonary Inflammatory Disease of Central South University;the National Key Clinical Specialty Construction Projects of China。

摘　　要：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.

关 键 词：DNAH10 MICE motile cilia mutation primary ciliary dyskinesia 

分 类 号：R32[医药卫生—人体解剖和组织胚胎学]