Am J Med Genet A. 2022 Jan;188(1):104-115. doi: 10.1002/ajmg.a.62497. Epub 2021 Sep 15.

Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.

American journal of medical genetics. Part A

Katherine A Inskeep, Yuri A Zarate, Danielle Monteil, Jurgen Spranger, Dan Doherty, Rolf W Stottmann, K Nicole Weaver

PMID: 34523780 DOI: 10.1002/ajmg.a.62497

Abstract

Primary ciliopathies are heterogenous disorders resulting from perturbations in primary cilia form and/or function. Primary cilia are cellular organelles which mediate key signaling pathways during development, such as the sonic hedgehog (SHH) pathway which is required for neuroepithelium and central nervous system development. Joubert syndrome is a primary ciliopathy characterized by cerebellar/brain stem malformation, hypotonia, and developmental delays. At least 35 genes are associated with Joubert syndrome, including the gene KIAA0753, which is part of a complex required for primary ciliogenesis. The phenotypic spectrum associated with biallelic pathogenic variants in KIAA0753 is broad and not well-characterized. We describe four individuals with biallelic pathogenic KIAA0753 variants, including five novel variants. We report in vitro results assessing the function of each variant indicating that mutant proteins are not fully competent to promote primary ciliogenesis. Ablation of KIAA0753 in vitro blocks primary ciliogenesis and SHH pathway activity. Correspondingly, KIAA0753 patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation. Our work expands the phenotypic spectrum of KIAA0753 ciliopathies and demonstrates the utility of patient-focused functional assays for proving causality of genetic variants.

© 2021 Wiley Periodicals LLC.

Keywords: Joubert syndrome; KIAA0753; ciliopathies

References

1. Abdelhamed, Z. A., Wheway, G., Szymanska, K., Natarajan, S., Toomes, C., Inglehearn, C., & Johnson, C. A. (2013). Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects. Human Molecular Genetics, 22(7), 1358-1372. - PubMed
2. Anvarian, Z., Mykytyn, K., Mukhopadhyay, S., Pedersen, L. B., & Christensen, S. T. (2019). Cellular signalling by primary cilia in development, organ function and disease. Nature Reviews. Nephrology, 15(4), 199-219. - PubMed
3. Aubusson-Fleury, A., Lemullois, M., de Loubresse, N. G., Laligne, C., Cohen, J., Rosnet, O., Jerka-Dziadosz, M., Beisson, J., & Koll, F. (2012). The conserved centrosomal protein FOR20 is required FOR assembly of the transition zone and basal body docking at the cell surface. Journal of Cell Science, 125(Pt 18), 4395-4404. - PubMed
4. Bachmann-Gagescu, R., Dempsey, J. C., Phelps, I. G., O'Roak, B. J., Knutzen, D. M., Rue, T. C., Ishak, G. E., Isabella, C. R., Gorden, N., Adkins, J., Boyle, E. A., de Lacy, N., O'Day, D., Alswaid, A., Ramadevi, A. R., Lingappa, L., Lourenco, C., Martorell, L., Garcia-Cazorla, A., … Doherty, D. (2015). Joubert syndrome: A model for untangling recessive disorders with extreme genetic heterogeneity. Journal of Medical Genetics, 52(8), 514-522. - PubMed
5. Baker, K., & Beales, P. L. (2009). Making sense of cilia in disease: The human ciliopathies. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 151C(4), 281-295. - PubMed
6. Bisgrove, B. W., & Yost, H. J. (2006). The roles of cilia in developmental disorders and disease. Development, 133(21), 4131-4143. - PubMed
7. Chevrier, V., Bruel, A. L., Van Dam, T. J., Franco, B., Lo Scalzo, M., Lembo, F., Audebert, S., Baudelet, E., Isnardon, D., Bole, A., Borg, J. P., Kuentz, P., Thevenon, J., Burglen, L., Faivre, L., Riviere, J. B., Huynen, M. A., Birnbaum, D., Rosnet, O., & Thauvin-Robinet, C. (2016). OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome. Human Molecular Genetics, 25(3), 497-513. - PubMed
8. Choi, Y., Sims, G. E., Murphy, S., Miller, J. R., & Chan, A. P. (2012). Predicting the functional effect of amino acid substitutions and indels. PLoS One, 7(10), e46688. - PubMed
9. Corbit, K. C., Shyer, A. E., Dowdle, W. E., Gaulden, J., Singla, V., Chen, M. H., Chuang, P. T., & Reiter, J. F. (2008). Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nature Cell Biology, 10(1), 70-76. - PubMed
10. Edgar, R. C. (2004a). MUSCLE: A multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics, 5, 113. - PubMed
11. Edgar, R. C. (2004b). MUSCLE: Multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Research, 32(5), 1792-1797. - PubMed
12. Elliott, K. H., & Brugmann, S. A. (2019). Sending mixed signals: Cilia-dependent signaling during development and disease. Developmental Biology, 447(1), 28-41. - PubMed
13. Faudi, E., Brischoux-Boucher, E., Huber, C., Dabudyk, T., Lenoir, M., Baujat, G., Michot, C., Van Maldergem, L., Cormier-Daire, V., & Piard, J. (2020). A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy. European Journal of Medical Genetics, 63(4), 103823. - PubMed
14. Gerdes, J. M., & Katsanis, N. (2008). Ciliary function and Wnt signal modulation. Current Topics in Developmental Biology, 85, 175-195. - PubMed
15. Gerdes, J. M., Liu, Y., Zaghloul, N. A., Leitch, C. C., Lawson, S. S., Kato, M., Beachy, P. A., Beales, P. L., DeMartino, G. N., Fisher, S., Badano, J. L., & Katsanis, N. (2007). Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nature Genetics, 39(11), 1350-1360. - PubMed
16. Grantham, R. (1974). Amino acid difference formula to help explain protein evolution. Science, 185(4154), 862-864. - PubMed
17. Hammarsjo, A., Wang, Z., Vaz, R., Taylan, F., Sedghi, M., Girisha, K. M., Chitayat, D., Neethukrishna, K., Shannon, P., Godoy, R., Gowrishankar, K., Lindstrand, A., Nasiri, J., Baktashian, M., Newton, P. T., Guo, L., Hofmeister, W., Pettersson, M., Chagin, A. S., … Ikegawa, S. (2017). Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies. Scientific Reports, 7(1), 15585. - PubMed
18. Hoover, A. N., Wynkoop, A., Zeng, H., Jia, J., Niswander, L. A., & Liu, A. (2008). C2cd3 is required for cilia formation and hedgehog signaling in mouse. Development, 135(24), 4049-4058. - PubMed
19. Kent, W. J. (2002). BLAT-the BLAST-like alignment tool. Genome Research, 12(4), 656-664. - PubMed
20. Kodani, A., Yu, T. W., Johnson, J. R., Jayaraman, D., Johnson, T. L., Al-Gazali, L., Sztriha, L., Partlow, J. N., Kim, H., Krup, A. L., Dammermann, A., Krogan, N. J., Walsh, C. A., & Reiter, J. F. (2015). Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication. eLife, 4, e07519. - PubMed
21. May-Simera, H. L., & Kelley, M. W. (2012). Cilia, Wnt signaling, and the cytoskeleton. Cilia, 1(1), 7. - PubMed
22. Okuno, T., Yamabayashi, H., & Kogure, K. (2010). Comparison of intracellular localization of Nubp1 and Nubp2 using GFP fusion proteins. Molecular Biology Reports, 37(3), 1165-1168. - PubMed
23. Parisi, M. A. (2019). The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity. Translational Science of Rare Diseases, 4(1-2), 25-49. - PubMed
24. Park, S. M., Jang, H. J., & Lee, J. H. (2019). Roles of primary cilia in the developing brain. Frontiers in Cellular Neuroscience, 13, 218. - PubMed
25. Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013). Genome engineering using the CRISPR-Cas9 system. Nature Protocols, 8(11), 2281-2308. - PubMed
26. Romio, L., Fry, A. M., Winyard, P. J., Malcolm, S., Woolf, A. S., & Feather, S. A. (2004). OFD1 is a centrosomal/basal body protein expressed during mesenchymal-epithelial transition in human nephrogenesis. Journal of the American Society of Nephrology, 15(10), 2556-2568. - PubMed
27. Schwarz, J. M., Cooper, D. N., Schuelke, M., & Seelow, D. (2014). MutationTaster2: Mutation prediction for the deep-sequencing age. Nature Methods, 11(4), 361-362. - PubMed
28. Singla, V., Romaguera-Ros, M., Garcia-Verdugo, J. M., & Reiter, J. F. (2010). Ofd1, a human disease gene, regulates the length and distal structure of centrioles. Developmental Cell, 18(3), 410-424. - PubMed
29. Stephen, J., Vilboux, T., Mian, L., Kuptanon, C., Sinclair, C. M., Yildirimli, D., Maynard, D. M., Bryant, J., Fischer, R., Vemulapalli, M., Mullikin, J. C., Program, N. C. S., Huizing, M., Gahl, W. A., Malicdan, M. C. V., & Gunay-Aygun, M. (2017). Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency. Human Genetics, 136(4), 399-408. - PubMed
30. Vilboux, T., Doherty, D. A., Glass, I. A., Parisi, M. A., Phelps, I. G., Cullinane, A. R., Zein, W., Brooks, B. P., Heller, T., Soldatos, A., Oden, N. L., Yildirimli, D., Vemulapalli, M., Mullikin, J. C., Nisc Comparative Sequencing, P., Malicdan, M. C. V., Gahl, W. A., & Gunay-Aygun, M. (2017). Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center. Genetics in Medicine, 19(8), 875-882. - PubMed
31. Willert, K., Brown, J. D., Danenberg, E., Duncan, A. W., Weissman, I. L., Reya, T., Yates, J. R., 3rd, & Nusse, R. (2003). Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature, 423(6938), 448-452. - PubMed

Publication Types

• Journal Article

Grant support

• Funding for this work is from the Cincinnati Children's Research Foundation (Rolf W. Stottmann) and NIH (R35GM121875; Rolf W. Stottmann). Danielle Monteil is a military service member. This work was prepared as part of her official duties. Title 17 U.S.C. 105 provides that "Copyright protection unde
• R35GM121875/GM/NIGMS NIH HHS/United States
• Cincinnati Children's Research Foundation
• R35GM121875/GM/NIGMS NIH HHS/United States