Disrupted intraflagellar transport due to IFT74 variants causes Joubert syndrome

Genet Med. 2021 Jun;23(6):1041-1049. doi: 10.1038/s41436-021-01106-z.

Minna Luo ^# ¹, Zaisheng Lin ^# ², Tian Zhu ^# ³, Minjun Jin ^# ⁴, Dan Meng ⁵, Ruida He ², Zongfu Cao ¹, Yue Shen ¹, Chao Lu ¹, Ruikun Cai ¹, Yong Zhao ⁶, Xueyan Wang ⁷, Hui Li ³, Shijing Wu ³, Xuan Zou ³, Guanjun Luo ⁶, Li Cao ⁸, Min Huang ², Huike Jiao ², Huafang Gao ¹, Ruifang Sui ⁹, Chengtian Zhao ¹⁰, Xu Ma ¹¹, Muqing Cao ¹²

Affiliations

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.
# Contributed equally.

PMID: 33531668 DOI: 10.1038/s41436-021-01106-z

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.

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