Analysis of USH2A gene mutation and clinical phenotype in families with Usher syndrome type 2 and retinitis pigmentosa_Chinese Journal of Ocular Fundus Diseases

Authors：

Shi Xiaomeng , Li Ya , Xie Kunpeng , You Ya ,  Lei Bo

Henan University People's Hospital, Henan Provincial People's Hospital, Henan Eye Institute & Henan Eye Hospital, Henan Clinical Research Center for Ophthalmic Diseases, Zhengzhou 450003, China;

Corresponding author：

Lei Bo, Email: bolei99@126.com

Keywords：

Usher syndromes; Retinitis pigmentosa; Genes, recessive; Mutation

DOI：

10.3760/cma.j.cn511434-20190912-00286

Video：

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Objective To observe the gene mutations and clinical phenotypes in patients with Usher syndrome type 2 (USH2) and retinitis pigmentosa (RP).Methods From August 2018 to January 2019, 4 patients and 11 normal family members from 3 families of USH2 and RP who visited Henan Eye Hospital were enrolled in the study. Detailed medical history was obtained and visual acuity, fundus color photography, OCT, visual field, full field ERG examination were performed. Among the three families, pedigree 1 was diagnosed with USH2, pedigree 2 and pedigree 3 were diagnosed with RP. The peripheral venous blood of patients and their family members were collected, and the whole genomic DNA was extracted. Targeted capture next generation sequencing analysis was performed on these members, and Sanger sequencing and family co-segregation were verified.Results In the family F1, the proband had symptoms of RP and sensorineural deafness. Sequencing revealed two heterozygous frameshift variants: c.13877-13880 del AGAC (p. Q4626P) in exon 64 and c.798 del T (p. F266L) in exon 5 of USH2A. Both patients of family 2 and 3 showed RP signs without deafness. Two heterozygous variants c.15178T＞C (p. S5060 P) in exon 70 and c.6986C＞A (p. P2329H) in exon 37, and a pathogenic heterozygous variant c.5836C＞T (p. R1946X) in exon 29 of USH2A were identified in family F2. A heterozygous missense variant c.14951C＞T (p. P4984L) in exon 68 and a variant c.11156G＞A (p. R3719H) in exon 57 of USH2A were found in family F3. The results of conservation analysis showed that the corresponding amino acid sites of USH2A p.Q4626P, p.F266L, p.S5060P, p.P2329H and p.P4984L were highly conserved in many species. Among these 7 pathogenic variants detected, M1-M4 and M6 were novel.Conclusions Mutation USH2A gene are the main cause of USH2 and non-syndromic RP. Different variants affect protein translation and synthesis, consequently causing different clinical phenotypes.

Citation： Shi Xiaomeng, Li Ya, Xie Kunpeng, You Ya, Lei Bo. Analysis of USH2A gene mutation and clinical phenotype in families with Usher syndrome type 2 and retinitis pigmentosa. Chinese Journal of Ocular Fundus Diseases, 2020, 36(3): 178-183. doi: 10.3760/cma.j.cn511434-20190912-00286 Copy

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2.	Vaché C, Besnard T, le Berre P, et al. Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy[J]. Hum Mutat, 2012, 33(1): 104-108. DOI: 10.1002/humu.21634.
3.	Liu S, Bi JG, Hu Y, et al. Targeted next generation sequencing identified novel loss-of-function mutations in MERTK gene in Chinese patients with retinitis pigmentosa[J/OL]. Mol Genet Genomic Med, 2019, 7(4): 00577[2019-02-20]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465654/. DOI: 10.1002/mgg3.577.
4.	Liquori A, Vaché C, Baux D, et al. Whole USH2A gene sequencing identifies several new deep intronic mutations[J]. Hum Mutat, 2016, 37(2): 184-193. DOI: 10.1002/humu.22926.
5.	van Wijk E, Pennings RJ, te Brinke H, 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 Hum Genet, 2004, 74(4): 738-744. DOI: 10.1086/383096.
6.	Wang Q, Zhu H, Xiao Z, et al. Expression of epidermal growth factor receptor is an independent prognostic factor for esophageal squamous cell carcinoma[J]. World J Surg Oncol, 2013, 11: 278. DOI: 10.1186/1477-7819-11-278.
7.	GeneReviews®[M]. Seattle (WA): University of Washington, Seattle, 1993.
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9.	Xu W, Dai H, Lu T, et al. Seven novel mutations in the long isoform of the USH2A gene in Chinese families with nonsyndromic retinitis pigmentosa and Usher syndrome type Ⅱ[J]. Mol Vis, 2011, 17: 1537-1552.
10.	Yan D, Liu XZ. Genetics and pathological mechanisms of Usher syndrome[J]. J Hum Genet, 2010, 55(6): 327-335. DOI: 10.1038/jhg.2010.29.
11.	Reiners J, Nagel-Wolfrum K, Jürgens K, et al. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease[J]. Exp Eye Res, 2006, 83(1): 97-119. DOI: 10.1016/j.exer.2005.11.010.
12.	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.
13.	Ng TK, Tang W, Cao Y, et al. Whole exome sequencing identifies novel USH2A mutations and confirms Usher syndrome 2 diagnosis in Chinese retinitis pigmentosa patients[J]. Sci Rep, 2019, 9(1): 5628. DOI: 10.1038/s41598-019-42105-0.
14.	McGee TL, Seyedahmadi BJ, 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): 499-506. DOI: 10.1136/jmg.2009.075143.
15.	王瑛, 黄辉, 樊宁, 等. 目标区域捕获技术鉴定一RP家系USH2A基因的新复合杂合突变[J]. 中华实验眼科杂志, 2016, 34(3): 244-247. DOI: 10.3760/cma.j.issn.2095-0160.2016.03.011.Wang Y, Huang H, Fan N, et al. Identification of novel compound heterozygous mutations of USH2A gene in a RP pedigree by targeted-capture next generation sequencing[J]. Chin J Exp Ophthalmol, 2016, 34(3): 244-247. DOI: 10.3760/cma.j.issn.2095-0160.2016.03.011.
16.	Méndez-Vidal C, González-Del Pozo M, Vela-Boza A, et al. Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa[J]. Mol Vis, 2013, 19: 2187-2195.

1. Huang L, Mao Y, Yang J, et al. Mutation screening of the USH2A gene in retinitis pigmentosa and USHER patients in a Han Chinese population[J]. Eye (Lond), 2018, 32(10): 1608-1614. DOI: 10.1038/s41433-018-0130-3.
2. Vaché C, Besnard T, le Berre P, et al. Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy[J]. Hum Mutat, 2012, 33(1): 104-108. DOI: 10.1002/humu.21634.
3. Liu S, Bi JG, Hu Y, et al. Targeted next generation sequencing identified novel loss-of-function mutations in MERTK gene in Chinese patients with retinitis pigmentosa[J/OL]. Mol Genet Genomic Med, 2019, 7(4): 00577[2019-02-20]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465654/. DOI: 10.1002/mgg3.577.
4. Liquori A, Vaché C, Baux D, et al. Whole USH2A gene sequencing identifies several new deep intronic mutations[J]. Hum Mutat, 2016, 37(2): 184-193. DOI: 10.1002/humu.22926.
5. van Wijk E, Pennings RJ, te Brinke H, 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 Hum Genet, 2004, 74(4): 738-744. DOI: 10.1086/383096.
6. Wang Q, Zhu H, Xiao Z, et al. Expression of epidermal growth factor receptor is an independent prognostic factor for esophageal squamous cell carcinoma[J]. World J Surg Oncol, 2013, 11: 278. DOI: 10.1186/1477-7819-11-278.
7. GeneReviews®[M]. Seattle (WA): University of Washington, Seattle, 1993.
8. Kremer H, van Wijk E, Märker T, et al. Usher syndrome: molecular links of pathogenesis, proteins and pathways[J]. Hum Mol Genet, 2006, 15(2): 262-270. DOI: 10.1093/hmg/ddl205.
9. Xu W, Dai H, Lu T, et al. Seven novel mutations in the long isoform of the USH2A gene in Chinese families with nonsyndromic retinitis pigmentosa and Usher syndrome type Ⅱ[J]. Mol Vis, 2011, 17: 1537-1552.
10. Yan D, Liu XZ. Genetics and pathological mechanisms of Usher syndrome[J]. J Hum Genet, 2010, 55(6): 327-335. DOI: 10.1038/jhg.2010.29.
11. Reiners J, Nagel-Wolfrum K, Jürgens K, et al. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease[J]. Exp Eye Res, 2006, 83(1): 97-119. DOI: 10.1016/j.exer.2005.11.010.
12. 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.
13. Ng TK, Tang W, Cao Y, et al. Whole exome sequencing identifies novel USH2A mutations and confirms Usher syndrome 2 diagnosis in Chinese retinitis pigmentosa patients[J]. Sci Rep, 2019, 9(1): 5628. DOI: 10.1038/s41598-019-42105-0.
14. McGee TL, Seyedahmadi BJ, 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): 499-506. DOI: 10.1136/jmg.2009.075143.
15. 王瑛, 黄辉, 樊宁, 等. 目标区域捕获技术鉴定一RP家系USH2A基因的新复合杂合突变[J]. 中华实验眼科杂志, 2016, 34(3): 244-247. DOI: 10.3760/cma.j.issn.2095-0160.2016.03.011.Wang Y, Huang H, Fan N, et al. Identification of novel compound heterozygous mutations of USH2A gene in a RP pedigree by targeted-capture next generation sequencing[J]. Chin J Exp Ophthalmol, 2016, 34(3): 244-247. DOI: 10.3760/cma.j.issn.2095-0160.2016.03.011.
16. Méndez-Vidal C, González-Del Pozo M, Vela-Boza A, et al. Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa[J]. Mol Vis, 2013, 19: 2187-2195.

Chinese Journal of Ocular Fundus Diseases

Analysis of USH2A gene mutation and clinical phenotype in families with Usher syndrome type 2 and retinitis pigmentosa

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