Pathology of Genetically Engineered and Other Mutant Mice. Группа авторов

[103]. Mutations involving multiple genes can be involved in individuals with Bardet–Biedl syndrome [104], and different mutations at the same locus of a single gene (CEP290) can result in three distinct disease syndromes (BBS, MKS, and NPHP) [1].

      Finally, it is important to know that truncating mutations often cause severe developmental defects that result in prenatal and perinatal mortality, whereas hypomorphic mutations are more likely to cause organ specific diseases that are degenerative rather than developmental [105]. Since complete loss of ciliopathy‐associated genes often results in early lethality, it may be necessary to generate mice carrying hypomorphic alleles with a range of strengths in order to model ciliopathies [1]. The genetic mechanisms that underlie ciliary functions and thus determine ciliopathy phenotypes are extremely complex, with gene locus heterogeneity, allelic effects, and modifier genes all contributing to influence both the type and severity of disease, and pleiotropic phenotypes [106]. To further complicate matters, a growing number of ciliopathies can be classified as second order ciliopathies [15]. These include ciliopathies that are caused by mutations in genes encoding proteins not present in cilia, but that do influence cilia formation or functions. For example, there are motile ciliopathies resulting from mutations affecting specific nonciliary proteins involved in the cytosolic assembly of axonemal dynein complexes before they are imported into cilia [15].

References

      1 Norris, D.P. and Grimes, D.T. (2012). Mouse models of ciliopathies: the state of the art. Dis. Models Mech. 5 (3): 299–312.

      2 Singla, V. and Reiter, J.F. (2006). The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 313 (5787): 629–633.

      3 Briscoe, J. and Therond, P.P. (2013). The mechanisms of Hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 14 (7): 416–429.

      4 Wallmeier, J., Nielsen, K.G., Kuehni, C.E. et al. (2020). Motile ciliopathies. Nat. Rev. Dis. Primers 6 (1): 77.

      5 Kempeneers, C. and Chilvers, M.A. (2018). To beat, or not to beat, that is question! The spectrum of ciliopathies. Pediatr. Pulmonol. 53 (8): 1122–1129.

      6 Davis, E.E. and Katsanis, N. (2012). The ciliopathies: a transitional model into systems biology of human genetic disease. Curr. Opin. Genet. Dev. 22 (3): 290–303.

      7  Schofield, P.N., Vogel, P., Gkoutos, G.V., and Sundberg, J.P. (2012). Exploring the elephant: histopathology in high‐throughput phenotyping of mutant mice. Dis. Models Mech. 5 (1): 19–25.

      8 Goetz, S.C. and Anderson, K.V. (2010). The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 11 (5): 331–344.

      9 Bloodgood, R.A. (2010). Sensory reception is an attribute of both primary cilia and motile cilia. J. Cell Sci. 123 (Pt 4): 505–509.

      10 Sigg, M.A., Menchen, T., Lee, C. et al. (2017). Evolutionary proteomics uncovers ancient associations of cilia with signaling pathways. Dev. Cell 43 (6): 744–62 e11.

      11 Heydeck, W., Fievet, L., Davis, E.E., and Katsanis, N. (2018). The complexity of the cilium: spatiotemporal diversity of an ancient organelle. Curr. Opin. Cell Biol. 55: 139–149.

      12 Christie, K.R. and Blake, J.A. (2018). Sensing the cilium, digital capture of ciliary data for comparative genomics investigations. Cilia 7: 3.

      13 van Dam, T.J., Wheway, G., and Slaats, G.G., SYSCILIA Study Group et al. (2013). The SYSCILIA gold standard (SCGSv1) of known ciliary components and its applications within a systems biology consortium. Cilia 2 (1): 7.

      14 Rohatgi, R., Milenkovic, L., and Scott, M.P. (2007). Patched1 regulates hedgehog signaling at the primary cilium. Science 317 (5836): 372–376.

      15 Reiter, J.F. and Leroux, M.R. (2017). Genes and molecular pathways underpinning ciliopathies. Nat. Rev. Mol. Cell Biol. 18 (9): 533–547.

      16 Goncalves, J. and Pelletier, L. (2017). The ciliary transition zone: finding the pieces and assembling the gate. Mol. Cells 40 (4): 243–253.

      17 Satir, P. and Christensen, S.T. (2007). Overview of structure and function of mammalian cilia. Annu. Rev. Physiol. 69: 377–400.

      18 Afzelius, B.A. (1976). A human syndrome caused by immotile cilia. Science 193 (4250): 317–319.

      19 Afzelius, B.A. (1999). Asymmetry of cilia and of mice and men. Int. J. Dev. Biol. 43 (4): 283–286.

      20 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.

      21 Vogel, P., Read, R.W., Hansen, G.M. et al. (2012). Congenital hydrocephalus in genetically engineered mice. Vet. Pathol. 49 (1): 166–181.

      22 Rott, H.D. (1979). Kartagener's syndrome and the syndrome of immotile cilia. Hum. Genet. 46 (3): 249–261.

      23 Zariwala, M.A., Omran, H., and Ferkol, T.W. (2011). The emerging genetics of primary ciliary dyskinesia. Proc. Am. Thorac. Soc. 8 (5): 430–433.

      24 Meeks, M. and Bush, A. (2000). Primary ciliary dyskinesia (PCD). Pediatr. Pulmonol. 29 (4): 307–316.

      25 Geremek, M. and Witt, M. (2004). Primary ciliary dyskinesia: genes, candidate genes and chromosomal regions. J. Appl. Genet. 45 (3): 347–361.

      26 Vogel, P., Hansen, G., Fontenot, G., and Read, R. (2010). Tubulin tyrosine ligase‐like 1 deficiency results in chronic rhinosinusitis and abnormal development of spermatid flagella in mice. Vet. Pathol. 47 (4): 703–712.

      27 Vogel, P., Read, R., Hansen, G.M. et al. (2010). Situs inversus in Dpcd/Poll−/−, Nme7−/−, and Pkd1l1−/− mice. Vet. Pathol. 47 (1): 120–131.

      28 Banizs, B., Pike, M.M., Millican, C.L. et al. (2005). Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus. Development 132 (23): 5329–5339.

      29 Ibanez‐Tallon, I., Pagenstecher, A., Fliegauf, M. et al. (2004). Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation. Hum. Mol. Genet. 13 (18): 2133–2141.

      30 Lee, L., Campagna, D.R., Pinkus, J.L. et al. (2008). Primary ciliary dyskinesia in mice lacking the novel ciliary protein Pcdp1. Mol. Cell. Biol. 28 (3): 949–957.

      31 Goto, J., Tezuka, T., Nakazawa, T. et al. (2008). Loss of Fyn tyrosine kinase on the C57BL/6 genetic background causes hydrocephalus with defects in oligodendrocyte development. Mol. Cell. Neurosci. 38 (2): 203–212.

      32 Itoh, K., Cheng, L., Kamei, Y. et al. (2004). Brain development in mice lacking L1–L1 homophilic adhesion. J. Cell Biol. 165 (1): 145–154.

      33 Rolf, B., Kutsche, M., and Bartsch, U. (2001). Severe hydrocephalus in L1‐deficient mice. Brain Res. 891 (1–2): 247–252.

      34 Nonaka, S., Tanaka, Y., Okada, Y. et al. (1998). Randomization of left–right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95 (6): 829–837.

      35 Capdevila, J., Vogan, K.J., Tabin, C.J., and Izpisua Belmonte, J.C. (2000). Mechanisms of left–right determination in vertebrates. Cell 101 (1): 9–21.

      36 Levin, M. (2005). Left–right asymmetry in embryonic development: a comprehensive review. Mech. Dev. 122 (1): 3–25.

      37 Mercola, M. and Levin, M. (2001). Left–right asymmetry determination in vertebrates. Annu. Rev. Cell Dev. Biol. 17: 779–805.

      38 Ramsdell, A.F. (2005). Left–right asymmetry and congenital cardiac defects: getting to the heart of the matter in vertebrate left–right axis determination. Dev. Biol. 288 (1): 1–20.

      39 Escalier, D. (2006). Knockout mouse models of sperm flagellum anomalies. Hum. Reprod. Update 12 (4): 449–461.

      40 Sironen, A., Shoemark, A., Patel, M. et al. (2020). Sperm defects in primary ciliary dyskinesia and related causes of male infertility. Cell. Mol. Life Sci. 77 (11): 2029–2048.

      41 Inaba, K. and Mizuno, K. (2016). Sperm dysfunction and ciliopathy. Reprod.