Advances of Usher syndrome and USH2A gene_Chinese Journal of Ocular Fundus Diseases

Authors：

Meng Xiang , Guo Tong ,  Yang Liping

Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China;

Corresponding author：

Yang Liping, Email: alexlipingyang@bjmu.edu.cn

Keywords：

Usher syndromes/genetics; Usher syndromes/etiology; Genes; Mutation; Review

DOI：

10.3760/cma.j.cn511434-20190123-00028

Video：

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Abstract Full text Figures/Tables Video References Cited by

Usher syndrome (USH) is the most common cause of deaf-blindness diseases characterized by sensorineural hearing loss and retinitis pigmentosa. Patients are clinically and genetically heterogeneous, however, there are no convincing methods for prevention and treatment. USH2A is the most common disease-causing gene among 14 genes related to Usher syndrome. Great progress has been achieved in the pathogenic mechanism, animal models studies, diagnosis, and treatments based on gene therapy, cells transplantation and antisense oligonucleotide-based splice correction. Mutations in USH2A result in defects in USH complex proteins which involved in the transport function of the peripheral cilia region. There is respective limitations in established mouse and zebrafish animal models. Two promising treatments of this disease are introduced. One is clinical transplantation of visual organs which induced from corrected patient-derived induced pluripotent stem cells by the CRISPR/Cas9 system and another one is the RNA splicing therapy based on antisense oligonucleotides.

Citation： Meng Xiang, Guo Tong, Yang Liping. Advances of Usher syndrome and USH2A gene. Chinese Journal of Ocular Fundus Diseases, 2020, 36(3): 236-241. doi: 10.3760/cma.j.cn511434-20190123-00028 Copy

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1. Kimberling WJ, Hildebrand MS, Shearer AE, et al. Frequency of Usher syndrome in two pediatric populations: implications for genetic screening of deaf and hard of hearing children[J]. Genet Med, 2010, 12(8): 512-516. DOI: 10.1097/GIM.0b013e3181e5afb8.
2. Millán JM, Aller E, Jaijo T, et al. An update on the genetics of Usher syndrome[J/OL]. J Ophthalmol, 2011, 2011: 417217[2011-10-23]. https://www.researchgate.net/publication/49754824_An_Update_on_the_Genetics_of_Usher_Syndrome. DOI: 10.1155/2011/417217.
3. Bonnet C, Grati MH, Marlin S, et al. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis[J]. Orphanet J Rare Dis, 2011, 6: 21. DOI: 10.1186/1750-1172-6-21.
4. Lenarduzzi S, Vozzi D, Morgan A, et al. Usher syndrome: an effective sequencing approach to establish a genetic and clinical diagnosis[J]. Hear Res, 2015, 320: 18-23. DOI: 10.1016/j.heares.2014.12.006.
5. Mcgee TL, Babak Jian S, Sweeney MO, et al. Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type Ⅱ or non-syndromic retinitis pigmentosa[J]. J Med Genet, 2010, 47(7): 499. DOI: 10.1136/jmg.2009.075143.
6. Jouret G, Poirsier C, Spodenkiewicz M, et al. Genetics of Usher syndrome: new insights from a meta-analysis[J]. Otol Neurotol, 2019, 40(1): 121-129. DOI: 10.1097/mao.0000000000002054.
7. Pearsall N, Bhattacharya G, Wisecarver J, et al. Usherin expression is highly conserved in mouse and human tissues[J]. H Res, 2002, 174(1): 55-63. DOI: 10.1016/s0378-5955(02)00635-4.
8. Erwin VW, Pennings RJE, Heleen TB, et al. Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type Ⅱ[J]. Am J Med Genet, 2004, 74(4): 738-744. DOI: 10.1086/383096.
9. Aller E, Jaijo T, Beneyto M, et al. Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type Ⅱ[J]. J Med Genet, 2006, 43(11): 55. DOI: 10.1136/jmg.2006.041764.
10. Tina M, Erwin VW, Nora O, et al. A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells[J]. Hum Mol Genet, 2008, 17(1): 71-86. DOI: 10.1093/hmg/ddm285.
11. Iman S, Eric D, Cataldo S, et al. Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice[J/OL]. J Cell Bio, 2012, 199(2): 381-399. https://rupress.org/jcb/article/199/2/381/37061/Localization-of-Usher-1-proteins-to-the. DOI: 10.1083/jcb.201202012.
12. Liu XQ, Bulgakov OV, Darrow KN, et al. Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells[J]. Proc Natl Acad Sci USA, 2007, 104(11): 4413-4418. DOI: 10.1073/pnas.0610950104.
13. Yang J, Liu X, Zhao Y, et al. Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss[J/OL]. PLoS Genet, 2010, 6(5): 1000955[2010-05-20]. 10.1371/journal.pgen.1000955">https://doi.org/10.1371/journal.pgen.1000955. DOI: 10.1371/journal.pgen.1000955.
14. Michalski N, Michel V, Bahloul A, et al. Molecular characterization of the ankle-link complex in cochlear hair cells and its role in the hair bundle functioning[J]. J Neurosci, 2007, 27(24): 6478-6488. DOI: 10.1523/JNEUROSCI.0342-07.2007.
15. Adato A, Lefèvre G, Delprat B, et al. Usherin, the defective protein in Usher syndrome type ⅡA, is likely to be a component of interstereocilia ankle links in the inner ear sensory cells[J]. Hum Mol Genet, 2005, 14(24): 3921-3932. DOI: 10.1093/hmg/ddi416.
16. Dona M, Slijkerman R, Lerner K, et al. Usherin defects lead to early-onset retinal dysfunction in zebrafish[J]. Exp Eye Res, 2018, 173: 148-159. DOI: 10.1016/j.exer.2018.05.015.
17. Qian C, Junhuang Z, Zuolian S, et al. Whirlin and PDZ domain-containing 7 (PDZD7) proteins are both required to form the quaternary protein complex associated with Usher syndrome type 2[J]. J Bio Chem, 2014, 289(52): 36070-36088. DOI: 10.1074/jbc.M114.610535.
18. van Wijk E, van der Zwaag B, Peters T, et al. The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1[J]. Hum Mol Genet, 2006, 15(5): 751-765. DOI: 10.1093/hmg/ddi490.
19. Kremer H, van Wijk E, Märker T, et al. Usher syndrome: molecular links of pathogenesis, proteins and pathways[J]. Hum Mol Genet, 2006, 15(Suppl 2): S262-270. DOI: 10.1093/hmg/ddl205.
20. Sorusch N, Bauß K, Plutniok J, et al. Characterization of the ternary Usher syndrome SANS/USH2A/whirlin protein complex[J]. Hum Mol Genet, 2017, 26(6): 1157-1172. DOI: 10.1093/hmg/ddx027.
21. Bhattacharya G, Kalluri R, Orten DJ, et al. A domain-specific usherin/collagen Ⅳ interaction may be required for stable integration into the basement membrane superstructure[J]. J Cell Sci, 2004, 117(Pt 2): 233-242. DOI: 10.1242/jcs.00850.
22. Ebermann I, Phillips JB, Liebau MC, et al. PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome[J]. J Clin Invest, 2010, 120(6): 1812-1823. DOI: 10.1172/JCI39715.
23. Schneider E, Märker T, Daser A, et al. Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment[J]. Hum Mol Genet, 2009, 18(4): 655-666. DOI: 10.1093/hmg/ddn395.
24. Dreyer B1, Brox V, Tranebjaerg L, et al. Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type Ⅱ[J]. Hum Mutat, 2008, 29(3): 451. DOI: 10.1002/humu.9524.
25. García-García G, Aller E, Jaijo T, et al. Novel deletions involving the USH2A gene in patients with Usher syndrome and retinitis pigmentosa[J]. Mol Vis, 2014, 20: 1398-1410. DOI: 10.1007/s10633-014-9452-z.
26. Lenassi E, Vincent A, Li Z, et al. A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants[J]. Eur J Hum Genet, 2015, 23(10): 1318-1327. DOI: 10.1038/ejhg.2014.283.
27. Sengillo JD, Cabral T, Schuerch K, et al. Electroretinography reveals difference in cone function between syndromic and nonsyndromic USH2A patients[J/OL]. Sci Rep, 2017, 7(1): 11170 [2017-09-11]. https://www.nature.com/articles/s41598-017-11679-y. DOI: 10.1038/s41598-017-11679-y.
28. Sandberg MA, Rosner B, Weigel-DiFranco C, et al. Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene[J]. Invest Ophthalmol Vis Sci, 2008, 49(12): 5532-5539. DOI: 10.1167/iovs.08-2009.
29. Sujirakul T, Lin MK, Duong J, et al. Multimodal imaging of central retinal disease progression in a 2-year mean follow-up of retinitis pigmentosa[J]. Am J Ophthalmol, 2015, 160(4): 786-798. DOI: 10.1016/j.ajo.2015.06.032.
30. Lu B, Wang S, Francis PJ, et al. Cell transplantation to arrest early changes in an USH2A animal model[J]. Invest Ophthalmol Vis Sci, 2010, 51(4): 2269-2276. DOI: 10.1167/iovs.09-4526.
31. Yao L, Zhang L, Qi LS, et al. The time course of deafness and retinal degeneration in a Kunming mouse model for usher syndrome[J/OL]. PLoS One, 2016, 11(5): 0155619[2016-05-17]. DOI: 10.1371/journal.pone.0155619.
32. El-Amraoui A, Petit C. Usher Ⅰ syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells[J]. J Cell Sci, 2005, 118(Pt 20): 4593-4603. DOI: 10.1242/jcs.02636.
33. Petit C. Usher syndrome: from genetics to pathogenesis[J]. Annu Rev Genomics Hum Genet, 2001, 2: 271-297. DOI: 10.1146/annurev.genom.2.1.271.
34. Slijkerman RW, Song F, Astuti GD, et al. The pros and cons of vertebrate animal models for functional and therapeutic research on inherited retinal dystrophies[J]. Prog Retin Eye Res, 2015, 48: 137-159. DOI: 10.1016/j.preteyeres.2015.04.004.
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