New mutation site c.361C > T of <i>RS1</i> gene in X-linked retinoschisis_Chinese Journal of Ocular Fundus Diseases

Authors：

Lu Rui , Yang Weihua , Jiang Qin , Li Xiumiao ,  Wang Chenghu

The Eye Hospital of Nanjing Medical University, Nanjing 210029, China;

Corresponding author：

Wang Chenghu, Email: wangchenghu1226@163.com

Keywords：

Retinoschisis; Genes; Mutation; RS1 gene

DOI：

10.3760/cma.j.cn511434-20210305-00124

Video：

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Objective To study the characteristics of the genotype and phenotypic in a family with X-linked retinoschisis (XLRS) due to RS1 mutation. Methods A retrospective clinical study. An XLRS family of 4 generations of 26 people were included in the study. Among them, 8 participants were males and 7 participants were females. Routine ophthalmologic examination was performed on 3 patients in the family including the proband and 12 patients with normal phenotype. Optical coherence tomography was performed in 2 of the 3 patients. Peripheral venous blood was extracted from all participants, whole-genome DNA was extracted, and potential pathogenic genes were screened by Panel sequencing. Conservative analysis, pathogenicity analysis and protein structure prediction were carried out by software tools. The pathogenicity of gene mutations was analyzed according to the American Society of Medical Genetics and Genomics (ACMG) guidelines. Results The proband was 3 years old. Optical coherence tomography (OCT) examination showed that the retinal core layer in the macular area of both eyes had a cystic change, which was segmented by vertical or oblique bridging tissue. The proband's uncle was 32 years old. OCT examination showed atrophy in the macular area of the left eye. The macular area of the right eye was cystoid, segmented by vertical or oblique bridging tissue. No abnormality was found in the fundus examination of the proband's parents and 10 members of his family. Panel sequencing showed that c.361C>T/ p.Q121X hemizygous mutation was found in the fifth exon of RS1 gene in the proband (Ⅳ3) and 2 patients (Ⅱ1, Ⅲ8). The mother was a heterozygous mutation carrier of the gene, while the father had no mutation. The mutant gene causes premature termination of RS1, a truncated protein encoding 224 amino acids to 120 amino acids. Of the 10 patients with normal fundus examination, 6 participants were normal. The mutation was carried by four people, which were women. Homology analysis of the protein sequence showed that the mutant site was highly conserved in 12 mammals. Three-dimensional structural analysis of RS1 protein showed that the c-terminal amino acid sequence of the mutant protein was more than 50% missing. Analysis of ACMG guidelines indicated that the mutation was pathogenic. Conclusion The RS1 mutation site c.361C>T/p.Q121X is a new mutation site of XLRS.

Citation： Lu Rui, Yang Weihua, Jiang Qin, Li Xiumiao, Wang Chenghu. New mutation site c.361C > T of RS1 gene in X-linked retinoschisis. Chinese Journal of Ocular Fundus Diseases, 2021, 37(11): 854-859. doi: 10.3760/cma.j.cn511434-20210305-00124 Copy

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2.	Sauer CG, Gehrig A, Warneke-Wittstock R, et al. Positional cloning of the gene associated with X-linked juvenile retinoschisis[J]. Nat Genet, 1997, 17(2): 164-170. DOI: 10.1038/ng1097-164.
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5.	Wu WW, Wong JP, Kast J, et al. RS1, a discoidin domain-containing retinal cell adhesion protein associated with X-linked retinoschisis, exists as a novel disulfide- linked octamer[J]. J Biol Chem, 2005, 280(11): 10721-10730. DOI: 10.1074/jbc.M413117200.
6.	Li MM, Datto M, Duncavage EJ, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the association for molecular pathology, American Society of Clinical Oncology, and College of American Pathologists[J]. J Mol Diagn, 2017, 19(1): 4-23. DOI: 10.1016/j.jmoldx.2016.10.002.
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11.	Stephenson K, Dockery A, Wynne N, et al. Multimodal imaging in a pedigree of X-linked retinoschisis with a novel RS1 variant[J/OL]. BMC Med Genet, 2018, 19(1): 195[2018-11-12]. https://pubmed.ncbi.nlm.nih.gov/30419843/. DOI: 10.1186/s12881-018-0712-8.
12.	蔡博, 刘洋, 朴顺玉, 等. RS1基因突变的X连锁视网膜劈裂症家系基因型和表型分析[J]. 中华实验眼科杂志, 2020, 38(4): 322-330. DOI: 10.3760/cma.j.cn115985-20190711-00307.Cai B, Liu Y, Piao SY, et al. A phenotype-genotype study of X-linked retinoschisis in RS1 mutations[J]. Chin J Exp Ophthalmol, 2020, 38(4): 322-330. DOI: 10.3760/cma.j.cn115985-20190711-00307.
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14.	张阳阳, 戴旭锋, 张华, 等. X连锁视网膜劈症分子遗传学研究与基因治疗的现状及进展[J]. 中华眼底病杂志, 2016, 32(6): 657-660. DOI: 10.3670/cma.j.issn.1005-1015.2016.06.027.Zhang YY, Dai XF, Zhang H, et al. Molecular genetics and gene therapy of X-linked congenital retinoschisis[J]. Chin J Ocul Fundus Dis, 2016, 32(6): 657-660. DOI: 10.3670/cma.j.issn.1005-1015.2016.06.027.
15.	Huang Y, Mei L, Gui B, et al. A novel deletion mutation in RS1 gene caused X-linked juvenile retinoschisis in a Chinese family[J]. Eye (Lond), 2014, 28(11): 1364-1369. DOI: 10.1038/eye.2014.196.
16.	Ambrosio L, Williams JS, Gutierrez A, et al. Carbonic anhydrase inhibition in X-linked retinoschisis: an eye on the photoreceptors[J/OL]. Exp Eye Res, 2021, 202: 108344[2020-11-10]. https://pubmed.ncbi.nlm.nih.gov/33186570/. DOI: 10.1016/j.exer.2020.108344.
17.	Piermarocchi S, Miotto S, Colavito D, et al. Long-term rearrangement of retinal structures in a novel mutation of X-linked retinoschisis[J]. Biomed Rep, 2017, 7(3): 241-246. DOI: 10.3892/br.2017.954.
18.	Molday RS. Focus on molecules: retinoschisin (RS1)[J]. Exp Eye Res, 2007, 84(2): 227-228. DOI: 10.1016/j.exer.2005.12.013.
19.	Hu QR, Huang LZ, Chen XL, et al. Genetic analysis and clinical features of X-linked retinoschisis in Chinese patients[J/OL]. Sci Rep, 2017, 7: 44060[2017-03-08]. https://pubmed.ncbi.nlm.nih.gov/28272453/. DOI: 10.1038/srep44060.
20.	Rahman N, Georgiou M, Khan KN, et al. Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options[J]. Br J Ophthalmol, 2020, 104(4): 451-460. DOI: 10.1136/bjophthalmol-2019-315086.

1. Sikkink SK, Biswas S, Parry NR, et al. X-linked retinoschisis: an update[J]. J Med Genet, 2007, 44(4): 225-232. DOI: 10.1136/jmg.2006.047340.
2. Sauer CG, Gehrig A, Warneke-Wittstock R, et al. Positional cloning of the gene associated with X-linked juvenile retinoschisis[J]. Nat Genet, 1997, 17(2): 164-170. DOI: 10.1038/ng1097-164.
3. Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis. The Retinoschisis Consortium[J]. Hum Mol Genet, 1998, 7(7): 1185-1192. DOI: 10.1093/hmg/7.7.1185.
4. Chen D, Xu T, Tu M, et al. Recapitulating X-linked juvenile retinoschisis in mouse model by knock-in patient-specific novel mutation[J/OL]. Front Mol Neurosci, 2018, 12, 10: 453[2018-01-12]. https://pubmed.ncbi.nlm.nih.gov/29379415/. DOI: 10.3389/fnmol.2017.00453.
5. Wu WW, Wong JP, Kast J, et al. RS1, a discoidin domain-containing retinal cell adhesion protein associated with X-linked retinoschisis, exists as a novel disulfide- linked octamer[J]. J Biol Chem, 2005, 280(11): 10721-10730. DOI: 10.1074/jbc.M413117200.
6. Li MM, Datto M, Duncavage EJ, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the association for molecular pathology, American Society of Clinical Oncology, and College of American Pathologists[J]. J Mol Diagn, 2017, 19(1): 4-23. DOI: 10.1016/j.jmoldx.2016.10.002.
7. Altschwager P, Ambrosio L, Swanson EA, et al. Juvenile macular degenerations[J]. Semin Pediatr Neurol, 2017, 24(2): 104-109. DOI: 10.1016/j.spen.2017.05.005.
8. Tsang SH, Sharma T. X-linked juvenile retinoschisis[J]. Adv Exp Med Biol, 2018, 1085: 43-48. DOI: 10.1007/978-3-319-95046-4_10.
9. Hu QR, Huang LZ, Chen XL, et al. X-linked retinoschisis in juveniles: follow-up by optical coherence tomography[J/OL]. Biomed Res Int, 2017, 2017: 1704623[2017-02-14]. https://pubmed.ncbi.nlm.nih.gov/28286756/. DOI: 10.1155/2017/1704623.
10. Chatziralli I, Theodossiadis G, Brouzas D, et al. Optical coherence tomography evolution in a case of X-linked juvenile retinoschisis: 15 years of follow-up[J]. Case Rep Ophthalmol, 2017, 8(3): 459-464. DOI: 10.1159/000480069.
11. Stephenson K, Dockery A, Wynne N, et al. Multimodal imaging in a pedigree of X-linked retinoschisis with a novel RS1 variant[J/OL]. BMC Med Genet, 2018, 19(1): 195[2018-11-12]. https://pubmed.ncbi.nlm.nih.gov/30419843/. DOI: 10.1186/s12881-018-0712-8.
12. 蔡博, 刘洋, 朴顺玉, 等. RS1基因突变的X连锁视网膜劈裂症家系基因型和表型分析[J]. 中华实验眼科杂志, 2020, 38(4): 322-330. DOI: 10.3760/cma.j.cn115985-20190711-00307.Cai B, Liu Y, Piao SY, et al. A phenotype-genotype study of X-linked retinoschisis in RS1 mutations[J]. Chin J Exp Ophthalmol, 2020, 38(4): 322-330. DOI: 10.3760/cma.j.cn115985-20190711-00307.
13. Zhang N, Peng Y, Zhou N, et al. A novel mutation in the RS1 gene in a Chinese family with X-linked congenital retinoschisis[J/OL]. Exp Ther Med, 2021, 21(2): 124[2020-12-03]. https://pubmed.ncbi.nlm.nih.gov/33335587/. DOI: 10.3892/etm.2020.9556.
14. 张阳阳, 戴旭锋, 张华, 等. X连锁视网膜劈症分子遗传学研究与基因治疗的现状及进展[J]. 中华眼底病杂志, 2016, 32(6): 657-660. DOI: 10.3670/cma.j.issn.1005-1015.2016.06.027.Zhang YY, Dai XF, Zhang H, et al. Molecular genetics and gene therapy of X-linked congenital retinoschisis[J]. Chin J Ocul Fundus Dis, 2016, 32(6): 657-660. DOI: 10.3670/cma.j.issn.1005-1015.2016.06.027.
15. Huang Y, Mei L, Gui B, et al. A novel deletion mutation in RS1 gene caused X-linked juvenile retinoschisis in a Chinese family[J]. Eye (Lond), 2014, 28(11): 1364-1369. DOI: 10.1038/eye.2014.196.
16. Ambrosio L, Williams JS, Gutierrez A, et al. Carbonic anhydrase inhibition in X-linked retinoschisis: an eye on the photoreceptors[J/OL]. Exp Eye Res, 2021, 202: 108344[2020-11-10]. https://pubmed.ncbi.nlm.nih.gov/33186570/. DOI: 10.1016/j.exer.2020.108344.
17. Piermarocchi S, Miotto S, Colavito D, et al. Long-term rearrangement of retinal structures in a novel mutation of X-linked retinoschisis[J]. Biomed Rep, 2017, 7(3): 241-246. DOI: 10.3892/br.2017.954.
18. Molday RS. Focus on molecules: retinoschisin (RS1)[J]. Exp Eye Res, 2007, 84(2): 227-228. DOI: 10.1016/j.exer.2005.12.013.
19. Hu QR, Huang LZ, Chen XL, et al. Genetic analysis and clinical features of X-linked retinoschisis in Chinese patients[J/OL]. Sci Rep, 2017, 7: 44060[2017-03-08]. https://pubmed.ncbi.nlm.nih.gov/28272453/. DOI: 10.1038/srep44060.
20. Rahman N, Georgiou M, Khan KN, et al. Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options[J]. Br J Ophthalmol, 2020, 104(4): 451-460. DOI: 10.1136/bjophthalmol-2019-315086.

Chinese Journal of Ocular Fundus Diseases

New mutation site c.361C > T of RS1 gene in X-linked retinoschisis

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