Volume 43 Issue 3
May  2022
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Zhi-Lin Ren, Hou-Bin Zhang, Lin Li, Zheng-Lin Yang, Li Jiang. Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations. Zoological Research, 2022, 43(3): 442-456. doi: 10.24272/j.issn.2095-8137.2021.387
Citation: Zhi-Lin Ren, Hou-Bin Zhang, Lin Li, Zheng-Lin Yang, Li Jiang. Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations. Zoological Research, 2022, 43(3): 442-456. doi: 10.24272/j.issn.2095-8137.2021.387

Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations

doi: 10.24272/j.issn.2095-8137.2021.387
Funds:  This work was supported by the Natural Science Foundation of China (81670893, 82121003), Science and Technology Department of Sichuan Province (2021JDZH0031), and Chinese Academy of Medical Sciences (2019-I2M-5-032)
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  • Mutations in serologically defined colon cancer autoantigen protein 8 (SDCCAG8) were first identified in retinal ciliopathy families a decade ago with unknown function. To investigate the pathogenesis of SDCCAG8-associated retinal ciliopathies in vivo, we employed CRISPR/Cas9-mediated homology-directed recombination (HDR) to generate two knock-in mouse models, Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467, which carry truncating mutations of the mouse Sdccag8, corresponding to mutations that cause Bardet-Biedl syndrome (BBS) and Senior-Løken syndrome (SLS) (c.696T>G p.Y232X and c.1339–1340insG p.E447GfsX463) in humans, respectively. The two mutant Sdccag8 knock-in mice faithfully recapitulated human SDCCAG8-associated BBS phenotypes such as rod-cone dystrophy, cystic renal disorder, polydactyly, infertility, and growth retardation, with varied age of onset and severity depending on the hypomorphic strength of the Sdccag8 mutations. To the best of our knowledge, these knock-in mouse lines are the first BBS mouse models to present with the polydactyly phenotype. Major phototransduction protein mislocalization was also observed outside the outer segment after initiation of photoreceptor degeneration. Impaired cilia were observed in the mutant photoreceptors, renal epithelial cells, and mouse embryonic fibroblasts derived from the knock-in mouse embryos, suggesting that SDCCAG8 plays an essential role in ciliogenesis, and cilium defects are a primary driving force of SDCCAG8-associated retinal ciliopathies.
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  • [1]
    Adams NA, Awadein A, Toma HS. 2007. The retinal ciliopathies. Ophthalmic Genetics, 28(3): 113−125. doi: 10.1080/13816810701537424
    Airik R, Schueler M, Airik M, Cho J, Ulanowicz KA, Porath JD, et al. 2016. SDCCAG8 interacts with RAB effector proteins RABEP2 and ERC1 and is required for hedgehog signaling. PLoS One, 11(5): e0156081. doi: 10.1371/journal.pone.0156081
    Airik R, Slaats GG, Guo Z, Weiss AC, Khan N, Ghosh A, et al. 2014. Renal-retinal ciliopathy gene Sdccag8 regulates DNA damage response signaling. Journal of the American Society of Nephrology, 25(11): 2573−2583. doi: 10.1681/ASN.2013050565
    Anderson DH, Fisher SK, Steinberg RH. 1978. Mammalian cones: disc shedding, phagocytosis, and renewal. Investigative Ophthalmology & Visual Science, 17(2): 117−133.
    Atala A, Freeman MR, Mandell J, Beier DR. 1993. Juvenile cystic kidneys (jck): a new mouse mutation which causes polycystic kidneys. Kidney International, 43(5): 1081−1085. doi: 10.1038/ki.1993.151
    Attanasio M, Uhlenhaut NH, Sousa VH, O'Toole JF, Otto E, Anlag K, et al. 2007. Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nature Genetics, 39(8): 1018−1024. doi: 10.1038/ng2072
    Bachmann-Gagescu R, Neuhauss SC. 2019. The photoreceptor cilium and its diseases. Current Opinion in Genetics & Development, 56: 22−33.
    Bahmanpour Z, Daneshmandpour Y, Kazeminasab S, Khalil Khalili S, Alehabib E, Chapi M, et al. 2021. A novel splice site mutation in the SDCCAG8 gene in an Iranian family with Bardet-Biedl syndrome. International Journal of Ophthalmology, 41(2): 389−397. doi: 10.1007/s10792-020-01588-x
    Banan M. 2020. Recent advances in CRISPR/Cas9-mediated knock-ins in mammalian cells. Journal of Biotechnology, 308: 1−9. doi: 10.1016/j.jbiotec.2019.11.010
    Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. 1999. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. Journal of Medical Genetics, 36(6): 437−446.
    Billingsley G, Vincent A, Deveault C, Heon E. 2012. Mutational analysis of SDCCAG8 in Bardet-Biedl syndrome patients with renal involvement and absent polydactyly. Ophthalmic Genetics, 33(3): 150−154. doi: 10.3109/13816810.2012.689411
    Braun DA, Hildebrandt F. 2017. Ciliopathies. Cold Spring Harbor Perspectives in Biology, 9(3): a028191. doi: 10.1101/cshperspect.a028191
    Bujakowska KM, Liu Q, Pierce EA. 2017. Photoreceptor cilia and retinal ciliopathies. Cold Spring Harbor Perspectives in Biology, 9(10): a028274. doi: 10.1101/cshperspect.a028274
    Chen HY, Kelley RA, Li TS, Swaroop A. 2021. Primary cilia biogenesis and associated retinal ciliopathies. Seminars in Cell & Developmental Biology, 110: 70−88.
    Chen HY, Welby E, Li TS, Swaroop A. 2019. Retinal disease in ciliopathies: recent advances with a focus on stem cell-based therapies. Translational Science of Rare Diseases, 4(1-2): 97−115. doi: 10.3233/TRD-190038
    Di Gioia SA, Letteboer SJF, Kostic C, Bandah-Rozenfeld D, Hetterschijt L, Sharon D, et al. 2012. FAM161A, associated with retinitis pigmentosa, is a component of the cilia-basal body complex and interacts with proteins involved in ciliopathies. Human Molecular Genetics, 21(23): 5174−5184. doi: 10.1093/hmg/dds368
    Dong SL, Maziveyi M, Alahari SK. 2015. Primary tumor and MEF Cell Isolation to Study Lung Metastasis. Journal of Visualized Experiments, (99): e52609.
    Eckmiller MS. 1987. Cone outer segment morphogenesis: taper change and distal invaginations. Journal of Cell Biology, 105(5): 2267−2277. doi: 10.1083/jcb.105.5.2267
    Forsythe E, Beales PL. 2013. Bardet–Biedl syndrome. European Journal of Human Genetics, 21(1): 8−13. doi: 10.1038/ejhg.2012.115
    Gonzalez S, Gupta J, Villa E, Mallawaarachchi I, Rodriguez M, Ramirez M, et al. 2016. Replication of genome-wide association study (GWAS) susceptibility loci in a Latino bipolar disorder cohort. Bipolar Disorders, 18(6): 520−527. doi: 10.1111/bdi.12438
    Halbritter J, Bizet AA, Schmidts M, Porath JD, Braun DA, Gee HY, et al. 2013a. Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans. American Society of Human Genetics, 93(5): 915-925.
    Halbritter J, Porath JD, Diaz KA, Braun DA, Kohl S, Chaki M, et al. 2013b. Identification of 99 novel mutations in a worldwide cohort of 1, 056 patients with a nephronophthisis-related ciliopathy. Human Genetics, 132(8): 865−884. doi: 10.1007/s00439-013-1297-0
    Hamshere ML, Walters JTR, Smith R, Richards AL, Green E, Grozeva D, et al. 2013. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Molecular Psychiatry, 18(6): 708−712. doi: 10.1038/mp.2012.67
    Hartong DT, Berson EL, Dryja TP. 2006. Retinitis pigmentosa. The Lancet, 368(9549): 1795−1809. doi: 10.1016/S0140-6736(06)69740-7
    Hildebrandt F, Attanasio M, Otto E. 2009. Nephronophthisis: disease mechanisms of a ciliopathy. Journal of the American Society of Nephrology, 20(1): 23−35. doi: 10.1681/ASN.2008050456
    Hsu PD, Lander ES, Zhang F. 2014. Development and applications of CRISPR-Cas9 for genome engineering. Cell, 157(6): 1262−1278. doi: 10.1016/j.cell.2014.05.010
    Hurd TW, Hildebrandt F. 2011. Mechanisms of nephronophthisis and related ciliopathies. Nephron Experimental Nephrology, 118(1): e9−e14. doi: 10.1159/000320888
    Insolera R, Shao W, Airik R, Hildebrandt F, Shi SH. 2014. SDCCAG8 regulates pericentriolar material recruitment and neuronal migration in the developing cortex. Neuron, 83(4): 805−822. doi: 10.1016/j.neuron.2014.06.029
    Jiang L, Zhang HB, Dizhoor AM, Boye SE, Hauswirth WW, Frederick JM, et al. 2011. Long-term RNA interference gene therapy in a dominant retinitis pigmentosa mouse model. Proceedings of the National Academy of Sciences of the United States of America, 108(45): 18476−18481. doi: 10.1073/pnas.1112758108
    Kang HG, Lee HK, Ahn YH, Joung JG, Nam J, Kim NKD, et al. 2016. Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy. Experimental & Molecular Medicine, 48(8): e251.
    Kenedy AA, Cohen KJ, Loveys DA, Kato GJ, Dang CV. 2003. Identification and characterization of the novel centrosome-associated protein CCCAP. Gene, 303: 35−46. doi: 10.1016/S0378-1119(02)01141-1
    Koenekoop RK, Cremers FPM, den Hollander AI. 2007. Leber congenital amaurosis: ciliary proteins on the move. Ophthalmic Genetics, 28(3): 111−112. doi: 10.1080/13816810701537457
    Kumaran N, Moore AT, Weleber RG, Michaelides M. 2017. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. British Journal of Ophthalmology, 101(9): 1147−1154. doi: 10.1136/bjophthalmol-2016-309975
    May-Simera H, Nagel-Wolfrum K, Wolfrum U. 2017. Cilia – The sensory antennae in the eye. Progress in Retinal and Eye Research, 60: 144−180. doi: 10.1016/j.preteyeres.2017.05.001
    Norris DP, Grimes DT. 2012. Mouse models of ciliopathies: the state of the art. Disease Models & Mechanisms, 5(3): 299−312.
    Otto EA, Hurd TW, Airik R, Chaki M, Zhou WB, Stoetzel C, et al. 2010. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nature Genetics, 42(10): 840−850. doi: 10.1038/ng.662
    Patil H, Tserentsoodol N, Saha A, Hao Y, Webb M, Ferreira PA. 2012. Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons. Cell Death & Disease, 3(7): e355.
    Reiter JF, Leroux MR. 2017. Genes and molecular pathways underpinning ciliopathies. Nature Reviews Molecular Cell Biology, 18(9): 533−547. doi: 10.1038/nrm.2017.60
    Rix S, Calmont A, Scambler PJ, Beales PL. 2011. An Ift80 mouse model of short rib polydactyly syndromes shows defects in hedgehog signalling without loss or malformation of cilia. Human Molecular Genetics, 20(7): 1306−1314. doi: 10.1093/hmg/ddr013
    Schaefer E, Zaloszyc A, Lauer J, Durand M, Stutzmann F, Perdomo-Trujillo Y, et al. 2011. Mutations in SDCCAG8/NPHP10 cause bardet-biedl syndrome and are associated with penetrant renal disease and absent polydactyly. Molecular Syndromology, 1(6): 273−281.
    Shamseldin HE, Shaheen R, Ewida N, Bubshait DK, Alkuraya H, Almardawi E, et al. 2020. The morbid genome of ciliopathies: an update. Genetics in Medicine, 22(6): 1051−1060. doi: 10.1038/s41436-020-0761-1
    Stokman M, Lilien M, Knoers N. 2016. Nephronophthisis. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, et al. GeneReviews® [Internet]. Seattle: University of Washington .
    Tay SA, Vincent AL. 2020. Senior-Løken syndrome and intracranial hypertension. Ophthalmic Genetics, 41(4): 354−357. doi: 10.1080/13816810.2020.1766086
    Verbakel SK, van Huet RAC, Boon CJF, den Hollander AI, Collin RWJ, Klaver CCW, et al. 2018. Non-syndromic retinitis pigmentosa. Progress in Retinal and Eye Research, 66: 157−186. doi: 10.1016/j.preteyeres.2018.03.005
    Watanabe Y, Fujinaga S, Sakuraya K, Morisada N, Nozu K, Iijima K. 2019. Rapidly Progressive Nephronophthisis in a 2-Year-Old Boy with a Homozygous SDCCAG8 Mutation. Tohoku Journal of Experimental Medicine, 249(1): 29−32. doi: 10.1620/tjem.249.29
    Weihbrecht K, Goar WA, Carter CS, Sheffield VC, Seo S. 2018. Genotypic and phenotypic characterization of the Sdccag8Tn(sb-Tyr)2161B. CA1C2Ove mouse model. PLoS One, 13(2): e0192755. doi: 10.1371/journal.pone.0192755
    Wright AF, Chakarova CF, Abd El-Aziz MM, Bhattacharya SS. 2010. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nature Reviews Genetics, 11(4): 273−284. doi: 10.1038/nrg2717
    Yamamura T, Morisada N, Nozu K, Minamikawa S, Ishimori S, Toyoshima D, et al. 2017. Rare renal ciliopathies in non-consanguineous families that were identified by targeted resequencing. Clinical and Experimental Nephrology, 21(1): 136−142. doi: 10.1007/s10157-016-1256-x
    Zaghloul NA, Katsanis N. 2009. Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. The Journal of Clinical Investigation, 119(3): 428−437. doi: 10.1172/JCI37041
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