Clinical features and identification of gene mutation in families with familial exudative vitreoretinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Tongmei ,  Han Mei , Ying Ming , Hao Peng , Han Ruifang

Tianjin Eye Hospital, Clinical College of Ophthalmology Tianjin Medical University, Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin 300020, China;

Corresponding author：

Han Mei, Email: hanmay69@sina.com

Keywords：

Retinal diseases/genetics; Retinal diseases/etiology; Genes; Mutation; Sequence analysis

DOI：

10.3760/cma.j.issn.1005-1015.2018.06.007

Video：

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ObjectiveTo identify mutations in NDP, FZD4, LRP5, TSPAN12 in Chinese families with familial exudative vitreoretinopathy (FEVR) and observe the clinical features.MethodsRetrospective case series study. The 9 patients (18 eyes) and 5 normal members from 4 unrelated families were included in the study. The patients medical history and family history were collected in detail. All patients underwent best corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus colorized photography, fundus fluorescein angiography (FFA). Genomic DNA were collected from all the patients. Mutations were detected by directly sequencing to the whole coding region and exon-intron boundaries of NDP, FZD4, LRP5 and TSPAN12 gene. Polyphen and SIFT programs were used to predict the effects on the structure and functional properties of mutant protein.ResultsThere were two affected individuals in the family 2 carried LRP5 gene mutation [c.1330C＞T (p.R444C )] in exon 6 by sequence analysis. A score of 0.882 was acquired by Polyphen program analysis. And the missense change was predicted to be pathogenic by SIFT. Fundus changes of the proband showed angioplasia, tortuosity of peripheral vessels. And temporal dragging of the optic disc, peripheral avascular zone, neovascularization were found in FFA. Brush-like and straight of peripheral vessels were found in Ⅰ1. No variant was found in NDP, FZD4 and TSPAN12 gene.ConclusionOur study supports the gene mutation c.1330C＞T (p.R444C) of LRP5 is pathogenesis of FEVR. Patients with the same mutation could have variable phenotypic characteristics.

Citation： Zhang Tongmei, Han Mei, Ying Ming, Hao Peng, Han Ruifang. Clinical features and identification of gene mutation in families with familial exudative vitreoretinopathy. Chinese Journal of Ocular Fundus Diseases, 2018, 34(6): 556-561. doi: 10.3760/cma.j.issn.1005-1015.2018.06.007 Copy

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6.	Pefkianaki M, Hasanreisoglu M, Suchy SF, et al. Familial exudative vitreoretinopathy with a novel LRP5 mutation[J]. J Pediatr Ophthalmol Strabismus, 2016, 53: 39-42. DOI: 10.3928/01913913-20160719-02.
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9.	Fei P, Zhang Q , Huang L, et al. Identification of two novel LRP5 mutations in families with familial exudative vitreoretinopathy[J]. Mol Vis, 2014, 29(3): 395-409.
10.	Drenser KA, Dailey W, Vinekar A, et al. Clinical presentation and genetic correlation of patients with mutations affecting the FZD4 gene[J]. Arch Ophthalmol.2009.127(10): 1649-1654. DOI: 10.1001/archophthalmol.2009.322.
11.	李忆安, 张琦, 彭婕, 等. 卷曲蛋白4联合低密度脂蛋白相关蛋白5基因突变的家族性渗出性玻璃体视网膜病变二例[J]. 中华眼底病杂志, 2016, 32(1): 79-81. DOI: 10.3760/cma.j.issn.1005-1015.2016.01.019.Li YA, Zhang Q, Peng J, et al. Mutations in the FZD4 and LRP5 Gene with Familial Exudative Vitreoretinopathy: a report of two cases[J].Chin J Ocul Fundus Dis, 2016, 32(1): 79-81. DOI: 10.3760/cma.j.issn.1005-1015.2016.01.019.
12.	Sızmaz S, Yonekawa Y, T Trese M, et al. Familial exudative vitreoretinopathy[J]. Turk J Ophthalmol, 2015, 45(4): 164-168. DOI: 10.4274/tjo.67699.
13.	Chen ZY, Hendriks RW, Jobling MA, et al. Isolation and characterization of a candidate gene for Norrie disease[J].Nat Genet, 1992, 1(6): 204-208. DOI: 10.1038/ng0692-204.
14.	Seo SH, Yu YS, Park SW, et al. Molecular characterization of FZD4, LRP5, and TSPAN12 in familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2015, 56(9): 5143-5151. DOI: 10.1167/iovs.14-15680.
15.	Garcia-España A, Chung PJ, Sarkar IN, et al. Appearance of new tetraspanin genes during vertebrate evolution[J]. Genomics, 2008, 91(3): 326-334. DOI: 10.1016/j.ygeno.2007.12.005.
16.	Kondo H , Kusaka S, Yoshinaga A, et al. Mutations in the TSPAN12 gene in japanese patients with familial exudative vitreoretinopathy[J]. Am J Ophthalmol, 2011, 151(10): 1095-1100. DOI: 10.1016/j.ajo.2010.11.026.
17.	Junge HJ, Yang S, Burton JR, et al.TSPAN12 regulates retinal vascular development by promoting norrin but not Wnt induced FZD4/beta-catenin signaling[J].Cell, 2009, 299(11): 311-139. DOI: 10.1016/j.cell.2009.07.048.

1. Li JK, Fei P, Li Y, et al. Identification of novel KIF11 mutations in patients with familial exudative vitreoretinopathy and a phenotypic analysis[J/OL]. Sci Rep, 2016, 6: 26564[2016-05-23]. https://www.nature.com/articles/srep26564. DOI: 10.1038/srep26564.
2. Musada GR, Syed H, Jalali S, et al. Mutation spectrum of the FZD-4, TSPAN12 and ZNF408 genes in Indian FEVR patients[J]. BMC Ophthalmol, 2016, 17(16): 90. DOI: 10.1186/s12886-016-0236-y.
3. Nikopoulos K, Gilissen C, Hoischen A, et al. Next generation sequencing o f a 40 Mb linkage interval reveals TSPAN 12 mutations in patients with familial exudative vitreoretinopathy[J].Am J Hum Genet, 2010, 86(10): 240-247. DOI: 10.1016/j.ajhg.2009.12.016.
4. Kondo H, Kusaka S, Yoshinaga A, et al. Genetic variants of FZD4 and LRP5 genes in patients with advanced retinopathy of prematurity[J]. Mol.Vis, 2013, 19(13), 476-485.
5. Pendergast SD, Trese MT. Familial exudative vitreoretinopathy:results of surgical management[J]. Ophthalmology, 1998, 105(6): 1015-1023. DOI: 10.1016/S0161-6420(98)96002-X.
6. Pefkianaki M, Hasanreisoglu M, Suchy SF, et al. Familial exudative vitreoretinopathy with a novel LRP5 mutation[J]. J Pediatr Ophthalmol Strabismus, 2016, 53: 39-42. DOI: 10.3928/01913913-20160719-02.
7. Leonard B, Scott E. Harley小儿眼科学[M]. 谢立信, 译.5版. 北京:人民卫生出版社, 2009: 59-60.Leonard B, Scott E. Harley’s pediatric ophthalmology[M].Xie LX.Translation.5th ed. Beijing: People's Medical Publishing House, 2005: 66-67.
8. Qin M, Hayashi H, Oshima K, et al. Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy withmutations in the LRP5 and/ or FZD4 genes[J]. Hum Mutat, 2005, 26(3): 104-112. DOI: 10.1002/humu.20191.
9. Fei P, Zhang Q , Huang L, et al. Identification of two novel LRP5 mutations in families with familial exudative vitreoretinopathy[J]. Mol Vis, 2014, 29(3): 395-409.
10. Drenser KA, Dailey W, Vinekar A, et al. Clinical presentation and genetic correlation of patients with mutations affecting the FZD4 gene[J]. Arch Ophthalmol.2009.127(10): 1649-1654. DOI: 10.1001/archophthalmol.2009.322.
11. 李忆安, 张琦, 彭婕, 等. 卷曲蛋白4联合低密度脂蛋白相关蛋白5基因突变的家族性渗出性玻璃体视网膜病变二例[J]. 中华眼底病杂志, 2016, 32(1): 79-81. DOI: 10.3760/cma.j.issn.1005-1015.2016.01.019.Li YA, Zhang Q, Peng J, et al. Mutations in the FZD4 and LRP5 Gene with Familial Exudative Vitreoretinopathy: a report of two cases[J].Chin J Ocul Fundus Dis, 2016, 32(1): 79-81. DOI: 10.3760/cma.j.issn.1005-1015.2016.01.019.
12. Sızmaz S, Yonekawa Y, T Trese M, et al. Familial exudative vitreoretinopathy[J]. Turk J Ophthalmol, 2015, 45(4): 164-168. DOI: 10.4274/tjo.67699.
13. Chen ZY, Hendriks RW, Jobling MA, et al. Isolation and characterization of a candidate gene for Norrie disease[J].Nat Genet, 1992, 1(6): 204-208. DOI: 10.1038/ng0692-204.
14. Seo SH, Yu YS, Park SW, et al. Molecular characterization of FZD4, LRP5, and TSPAN12 in familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2015, 56(9): 5143-5151. DOI: 10.1167/iovs.14-15680.
15. Garcia-España A, Chung PJ, Sarkar IN, et al. Appearance of new tetraspanin genes during vertebrate evolution[J]. Genomics, 2008, 91(3): 326-334. DOI: 10.1016/j.ygeno.2007.12.005.
16. Kondo H , Kusaka S, Yoshinaga A, et al. Mutations in the TSPAN12 gene in japanese patients with familial exudative vitreoretinopathy[J]. Am J Ophthalmol, 2011, 151(10): 1095-1100. DOI: 10.1016/j.ajo.2010.11.026.
17. Junge HJ, Yang S, Burton JR, et al.TSPAN12 regulates retinal vascular development by promoting norrin but not Wnt induced FZD4/beta-catenin signaling[J].Cell, 2009, 299(11): 311-139. DOI: 10.1016/j.cell.2009.07.048.

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Clinical features and identification of gene mutation in families with familial exudative vitreoretinopathy

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