Minna Luo1, Zaisheng Lin2, Tian Zhu3, Minjun Jin4, Dan Meng5, Ruida He2, Zongfu Cao1, Yue Shen1, Chao Lu1, Ruikun Cai1, Yong Zhao6, Xueyan Wang7, Hui Li3, Shijing Wu3, Xuan Zou3, Guanjun Luo6, Li Cao8, Min Huang2, Huike Jiao2, Huafang Gao1, Ruifang Sui9, Chengtian Zhao10, Xu Ma11, Muqing Cao12. 1. National Human Genetic Resources Center, National Research Institute for Family Planning, Beijing, China. 2. Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 3. Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. 4. Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, China. 5. Tianjin Key Laboratory of Food and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China. 6. Child Rehabilitation Department, Nanhai Affiliated Maternity and Children's Hospital of Guangzhou University of TCM, Foshan, China. 7. Department of Prenatal Diagnosis, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China. 8. Child Healthcare Department, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China. 9. Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. hrfsui@163.com. 10. Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, China. chengtian_zhao@ouc.edu.cn. 11. National Human Genetic Resources Center, National Research Institute for Family Planning, Beijing, China. maxu_nhgrc@163.com. 12. Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. muqingcao@sjtu.edu.cn.
Abstract
PURPOSE: Ciliopathies are a group of disorders caused by defects of the cilia. Joubert syndrome (JBTS) is a recessive and pleiotropic ciliopathy that causes cerebellar vermis hypoplasia and psychomotor delay. Although the intraflagellar transport (IFT) complex serves as a key module to maintain the ciliary structure and regulate ciliary signaling, the function of IFT in JBTS remains largely unknown. We aimed to explore the impact of IFT dysfunction in JBTS. METHODS: Exome sequencing was performed to screen for pathogenic variants in IFT genes in a JBTS cohort. Animal model and patient-derived fibroblasts were used to evaluate the pathogenic effects of the variants. RESULTS: We identified IFT74 as a JBTS-associated gene in three unrelated families. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants. CONCLUSION: IFT74 is identified as a JBTS-related gene. Cellular and biochemical mechanisms are also provided.
PURPOSE: Ciliopathies are a group of disorders caused by defects of the cilia. Joubert syndrome (JBTS) is a recessive and pleiotropic ciliopathy that causes cerebellar vermis hypoplasia and psychomotor delay. Although the intraflagellar transport (IFT) complex serves as a key module to maintain the ciliary structure and regulate ciliary signaling, the function of IFT in JBTS remains largely unknown. We aimed to explore the impact of IFT dysfunction in JBTS. METHODS: Exome sequencing was performed to screen for pathogenic variants in IFT genes in a JBTS cohort. Animal model and patient-derived fibroblasts were used to evaluate the pathogenic effects of the variants. RESULTS: We identified IFT74 as a JBTS-associated gene in three unrelated families. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants. CONCLUSION: IFT74 is identified as a JBTS-related gene. Cellular and biochemical mechanisms are also provided.
Authors: Kimberly A Aldinger; Zachary Thomson; Ian G Phelps; Parthiv Haldipur; Mei Deng; Andrew E Timms; Matthew Hirano; Gabriel Santpere; Charles Roco; Alexander B Rosenberg; Belen Lorente-Galdos; Forrest O Gulden; Diana O'Day; Lynne M Overman; Steven N Lisgo; Paula Alexandre; Nenad Sestan; Dan Doherty; William B Dobyns; Georg Seelig; Ian A Glass; Kathleen J Millen Journal: Nat Neurosci Date: 2021-06-17 Impact factor: 28.771