Absence of CEP78 causes photoreceptor and sperm flagella impairments in mice and a human individual
Tianyu Zhu,
Yuxin Zhang,
Xunlun Sheng,
Xiangzheng Zhang,
Yu Chen,
Hongjing Zhu,
Yueshuai Guo,
Yaling Qi,
Yichen Zhao,
Qi Zhou,
Xue Chen,
Xuejiang Guo,
Chen Zhao
Affiliations
Tianyu Zhu
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Gusu School, Nanjing Medical University, Nanjing, China
Yuxin Zhang
Department of Ophthalmology and Vision Science, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
Xunlun Sheng
Gansu Aier Ophthalmiology and Optometry Hospital, Lanzhou, China; Ningxia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region, Third Clinical Medical College of Ningxia Medical University, Yinchuan, China
Xiangzheng Zhang
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Gusu School, Nanjing Medical University, Nanjing, China
Yu Chen
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Gusu School, Nanjing Medical University, Nanjing, China
Hongjing Zhu
Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
Yueshuai Guo
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Gusu School, Nanjing Medical University, Nanjing, China
Cone-rod dystrophy (CRD) is a genetically inherited retinal disease that can be associated with male infertility, while the specific genetic mechanisms are not well known. Here, we report CEP78 as a causative gene of a particular syndrome including CRD and male infertility with multiple morphological abnormalities of sperm flagella (MMAF) both in human and mouse. Cep78 knockout mice exhibited impaired function and morphology of photoreceptors, typified by reduced ERG amplitudes, disrupted translocation of cone arrestin, attenuated and disorganized photoreceptor outer segments (OS) disks and widen OS bases, as well as interrupted connecting cilia elongation and abnormal structures. Cep78 deletion also caused male infertility and MMAF, with disordered ‘9+2’ structure and triplet microtubules in sperm flagella. Intraflagellar transport (IFT) proteins IFT20 and TTC21A are identified as interacting proteins of CEP78. Furthermore, CEP78 regulated the interaction, stability, and centriolar localization of its interacting protein. Insufficiency of CEP78 or its interacting protein causes abnormal centriole elongation and cilia shortening. Absence of CEP78 protein in human caused similar phenotypes in vision and MMAF as Cep78−/− mice. Collectively, our study supports the important roles of CEP78 defects in centriole and ciliary dysfunctions and molecular pathogenesis of such multi-system syndrome.
