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.
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.
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.
IFT74 is identified as a JBTS-related gene. Cellular and biochemical mechanisms are also provided.
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The DNA, RNA, proteins, reagents, and the data in this study are available upon request.
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We thank the patients and their parents for their participation in this research and their permission for this publication. This work was supported by National Key Research and Development Program of China (2016YFC1000307) to X.M., National Natural Science Foundation of China (91954123, 31972887) to M.C., Clinical research projects of Shanghai Municipal Health Commission (20194Y0133) to M.C., National Nature Science Foundation of China (81873687) to R.S., CAMS Innovation Fund for Medical Sciences (CIFMS 2016-I2M-1-002) to R.S., Beijing Natural Science Foundation (7152116) to R.S., the Non-profit Central Research Institute Fund of National Research Institute for Family Planning (2020GJZ05) to M.L., National Natural Science Foundation of China (31701172) to D.M., Natural Science Foundation of Tianjin (18JCQNJC09900) to D.M., Qingdao National Laboratory for Marine Science and Technology (No.MS2019NO02) to C.Z., and the National Natural Science Foundation of China (31991194) to C.Z.
This study was performed in accordance with the contents of the Declaration of Helsinki and was approved by the Institutional Review Board of the National Research Institute for Family Planning (NRIFP) and Peking Union Medical College Hospital (PUMCH). All patient information, photos, and samples from the probands and/or their parents/sibling were collected after receiving written consent. All zebrafish experiments were conducted according to standard animal guidelines and were approved by the Institutional Animal Care Committee of Ocean University of China.
The authors declare no competing interests.
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Luo, M., Lin, Z., Zhu, T. et al. Disrupted intraflagellar transport due to IFT74 variants causes Joubert syndrome. Genet Med (2021). https://doi.org/10.1038/s41436-021-01106-z