Steven Lim Cho Pei
Brian Hon Yin Chung- 1Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United States
- 2Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- 3Hong Kong Genome Institute, Hong Kong, China
Editorial on the Research Topic
Genetics and mechanism of ciliopathies
Cilium is a microtubule-based hair-like organelle found on almost every type of cells in human body. These cilia can be motile (as in the cilia on respiratory tract epithelial cells) or non-motile (as in the cilia in nephrons of kidneys and photoreceptors on the retina of eyes). Meanwhile, single cilium (e.g., nephrons) or multiple copies of the cilia (e.g., epithelial cells in respiratory tract) are possible and observed in human cells. Despite of their highly complex structure, ciliary structure is conserved in vertebrate and consist of over 600 proteins (Fliegauf et al., 2007) orchestrating in a coordinated manner for its proper functions in development, signaling, homeostasis and sensory functions. Despite of its complicated structure, various signaling pathways were found to be involved in cilia formation, assembly and growth. For instance, hedgehog signaling (Huangfu et al., 2003), Wnt signaling (Clevers and Nusse, 2012), G-protein-coupled receptor signaling (Mykytyn and Askwith, 2017) etc. Were the well-known pathways involved in ciliopathies (Waters and Beales, 2011; Reiter and Leroux, 2017).
Since cilia are almost ubiquitously presence in all cell types in human body, it is not surprising that ciliopathies, which refers to any disorders that affects the ciliary function, cilia itself or its sub-structures, exhibit a large spectrum of anomalies in multiple organs and systems, for instance, brain, kidneys, liver, bone and eyes etc. Because of the complexity of proteins and signaling pathways involved in ciliopathies, the exact molecular mechanism is yet to be elucidated but it is certain that genetic variation like single nucleotide polymorphisms (SNPs), missense or nonsense mutations on cilia and/or related genes etc. played a major role in the pathogenesis. Thanks to the technology advancement in biotechnology and genetics on genome-editing, as well as the prevalence and readily available of next generation sequencing technique on exome and genome, the manuscripts included in this Research Topic can facilitate researchers to have a deeper understanding on the genetic variations in ciliopathies and provide ways for further verification of these changes with genome-editing and thus, test on the signaling pathways and molecular mechanism.
This Research Topic is dedicated to including works that explore any novel identification or characterization of genes, signaling pathways, transcriptomic analyses, and mechanisms on ciliary gene(s) and/or protein(s) involved in ciliopathies. Moreover, recent advancement in diagnosis of ciliary and/or cilia-related diseases, integrative analysis of publicly available data on ciliary genes and/or proteins, articles that summarize the existing data on ciliary pathologies were also included. A total of 13 manuscripts were included in this Research Topic.
Among these works, a number of novel studies revealing the causes and potential mechanisms of ciliopathies has been included. For instance, four reports described the novel variants identifications contributing to various manifestation of ciliopathies, such as nephronophthisis and kidney failure (by novel deletion of Glis2:c.560_574delACCATGTCAACGATT, p. H188_Y192del)) (Al Alawi et al.), asthenoteratozoospermia (by missense variant RSPH4A:c.2T>C, p. (Met1Thr) and nonsense variant RSPH4A:c.1774_1775del, p. (Leu592Aspfs*5) (Wang et al.), dynein axonemal assembly factor (DNAAF) -4 [by DNAAF4:c.733C>T, p.(Arg245*)] (Guo et al.), Meckel Gruber Syndrome (by splice site variant RPGRIP1L:c.776 + 1G > A/IVS6 + 1G > A) (Moreno-Leon et al.). These novel findings expanded the variants spectrum related to ciliopathies and provide some reference for others subjects who share the same variants in future.
While there are another three reports on variants that affect the renal and hepatic fibrocystic disease (by missense variant TULP3: c.1144C>T, p. (Arg382Trp)) (Jafari Khamirani et al.), showing skeletal ciliopathies (by missense variant IFT140 (NM_014,714.4) r.2765_2768del; p. (Tyr923Leufs*28)) (Walczak-Sztulpa et al.) and primary ciliary dyskinesia (PCD) in respiratory cilia [by missense variant DNAI2:c.740G>A; p. (Arg247Gln)] (Al-Mutairi et al.). All these case reports in this Research Topic, together with other previously published reports in the literatures, enhance our current understanding on the genetics variants contributed to ciliopathies.
Apart from the variant case reports, another three papers illustrated the vital tasks of cilia proteins in cilia assembly and functions were also included. For instance, Lennon et al. focused on the function of Dnaaf-4 and Dnaaf-6 in outer dynein arm (ODA) and a subset of inner dynein arm (IDA) assembly using drosophila model. While Schultz et al. studied the role of CFAP300 in dynein complex transport in motile cilia and in dynein arm assembly. Moreover, Nazlamova et al. showed in the CRISPR mutated PRPF6 and PRPF31 cell lines, patient-derived retinal organoid cultures and siRNA-treated retinal organotypic cultures that, mutation in the pre-mRNA splicing factor would resulted in defected microtubule and centrosome, ultimately leading to retinal degeneration. These works shed light on the potential mechanisms and signaling pathways for the pathogenesis of ciliopathies.
Furthermore, two articles in this Research Topic have highlighted the importance of genetic testing in the diagnosis of ciliopathies. The work of Chau et al. has demonstrated that genetic testing is essential in the diagnosis of early-onset bronchiectasis. While the project of Antony et al. indicated the significance of genetic diagnosis in a cohort of 37 cases laterality defect with defected left-right patterning. Their efforts have demonstrated that genetic diagnosis is key for the proper diagnosis of ciliopathies and would provide a valuable reference for the clinician.
In addition, it was delighted to have Rusterholz et al. to contribute an insightful review focusing on Joubert Syndrome, which is a rare cilia-related disorder characterized by cerebellar and brain stem malformation with other renal, retinal and skeletal manifestations. Their work has summarized and featured on what have been learnt in understanding Joubert Syndrome from different zebrafish models in the literatures.
In conclusion, despite many unknown and challenges in delineating the exact cause and molecular mechanism of ciliopathies, these studies in this Research Topic have greatly extended our current understanding on the genetic of ciliopathies and shed light on potential signaling pathway down to molecular level. A better understanding of the genetic and molecular mechanism of the disease is crucial for early diagnosis, appropriate treatment and improving the prognosis of patients, thus, this Research Topic would be valuable for further research and beneficial to the patients in future.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Acknowledgments
We thank all the authors and reviewers for their effort and contributions to this Research Topic.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
Clevers, H., and Nusse, R. (2012). Wnt/β-catenin signaling and disease. Cell 149 (6), 1192–1205. doi:10.1016/j.cell.2012.05.012
Fliegauf, M., Benzing, T., and Omran, H. (2007). When cilia go bad: Cilia defects and ciliopathies. Nat. Rev. Mol. Cell Biol. 8 (11), 880–893. doi:10.1038/nrm2278
Huangfu, D., Liu, A., Rakeman, A. S., Murcia, N. S., Niswander, L., and Anderson, K. V. (2003). Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426 (6962), 83–87. doi:10.1038/nature02061
Mykytyn, K., and Askwith, C. (2017). G-Protein-Coupled receptor signaling in cilia. Cold Spring Harb. Perspect. Biol. 9 (9), a028183. doi:10.1101/cshperspect.a028183
Reiter, J. F., and Leroux, M. R. (2017). Genes and molecular pathways underpinning ciliopathies. Nat. Rev. Mol. Cell Biol. 18 (9), 533–547. doi:10.1038/nrm.2017.60
Keywords: cilia, ciliopathies, primary ciliary dyskinesia, exome sequencing, single nucleotide polymorphisms, dynein
Citation: Pei SLC and Chung BHY (2022) Editorial: Genetics and mechanism of ciliopathies. Front. Genet. 13:1067168. doi: 10.3389/fgene.2022.1067168
Received: 11 October 2022; Accepted: 14 October 2022;
Published: 28 October 2022.
Edited and reviewed by:
Maxim B. Freidin, Queen Mary University of London, United KingdomCopyright © 2022 Pei and Chung. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Steven Lim Cho Pei, stevenpei@gmail.com; Brian Hon Yin Chung, bhychung@hku.hk