Gene mutation detection of the posterior microphthalmia-retinal pigment degeneration family_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Jie , Gao Shaohui , Xing Yasi , Lu Xiaonan ,  Dai Shuzhen

Department of Ophthalmology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan Eye Hospital, Henan Eye Institute, Henan Key Laboratory of Ophthalmology and Visual Science, Zhengzhou 450003, China;

Corresponding author：

Dai Shuzhen, Email: dsz997300056@163.com

Keywords：

Microphthalmos; Retinitis pigmentosa; MFRP gene mutation

DOI：

10.3760/cma.j.cn511434-20201124-00584

Video：

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Objective To identify the causative genes of the posterior microphthalmia-retinal pigment degeneration family. Methods A retrospective clinical study. One child (proband) and 3 family members of a family with posterior microphthalmia-retinitis pigmentosa diagnosed by clinical and genetic examination at Henan Provincial People's Hospital in July 2019 were included in the study. Medical history and family history, and draw pedigree of the patients was collected. Visual acuity, visual field, fundus color photography, optical coherence tomography and electroretinogram (ERG) were examined. The peripheral venous blood of the proband, his parents and sister, and extract the whole genome DNA was collected. Whole-exome sequencing was used to detect genetic variations, the suspected pathogenic variations were verified by Sanger sequencing, and the pathogenicity was determined by bioinformatics analysis. Results The parents discovered the proband was poor vision at the age of 10 months. At the age of 3, the best corrected visual acuity of the right eye and the left eye were 0.3 and 0.4, respectively. No abnormality was found in anterior segment. Extremely high hyperopia in both eyes. The axial length was 14.47 mm and 15.78 mm, respectively. The optic disc of both eyes was relatively small and flushed, retinal folds can be observed in macular area, and no obvious pigment deposition was found. ERG examination showed that the rod system response and the maximal combined response of both eyes decreased slightly to moderately, and the single-flash cone response and the 30 Hz flicker response decreased moderately to severely. Genetic analysis revealed two novel mutations in the membrane frizzled-related protein (MFRP) gene in the proband: c.363delC/p.Thr121Thrfs*16, c.1627C＞T/p .Gln543Stop,37 in exon 4 and 13, the former was a frameshift mutation, encoding 16 amino acids and then terminated, and the latter was an nonsense mutation, truncated 37 amino acids, both which were predicted to be pathogenic and segregate with disease. The mother and sister carried c.363delC, and the father carried c.1627C＞T. Conclusion MFRP gene c.363delC/p.Thr121Thrfs*16, c.1627C＞T/p.Gln543Stop, 37 compound heterozygous mutation may be the pathogenic gene of this family.

Citation： Li Jie, Gao Shaohui, Xing Yasi, Lu Xiaonan, Dai Shuzhen. Gene mutation detection of the posterior microphthalmia-retinal pigment degeneration family. Chinese Journal of Ocular Fundus Diseases, 2021, 37(11): 848-853. doi: 10.3760/cma.j.cn511434-20201124-00584 Copy

1.	Ghose S, Sachdev MS, Kumar H. Bilateral nanophthalmos, pigmentary retinal dystrophy, and angle closure glaucoma-a new syndrome?[J]. Br J Ophthalmol, 1985, 69(8): 624-628. DOI: 10.1136/bjo.69.8.624.
2.	Altintaş AK, Acar MA, Yalvaç IS, et al. Autosomal recessive nanophthalmos[J]. Acta Ophthalmol Scand, 1997, 75(3): 325-328. DOI: 10.1111/j.1600-0420.1997.tb00788.x.
3.	Källén B, Tornqvist K. The epidemiology of anophthalmia and microphthalmia in Sweden[J]. Eur J Epidemiol, 2005, 20(4): 345-350. DOI: 10.1007/s10654-004-6880-1.
4.	Hornby SJ, Xiao Y, Gilbert CE, et al. Causes of childhood blindness in the People's Republic of China: results from 1131 blind school students in 18 provinces[J]. Br J Ophthalmol, 1999, 83(8): 929-932. DOI: 10.1136/bjo.83.8.929.
5.	Prasov L, Guan B, Ullah E, et al. Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort[J/OL]. Sci Rep, 2020, 10(1): 19986[2020-11-17]. https://pubmed.ncbi.nlm.nih.gov/33203948/. DOI: 10.1038/s41598-020-76725-8.
6.	Won J, Smith RS, Peachey NS, et al. Membrane frizzled-related protein is necessary for the normal development and maintenance of photoreceptor outer segments[J]. Vis Neurosci, 2008, 25(4): 563-574. DOI: 10.1017/S0952523808080723.
7.	Carricondo PC, Andrade T, Prasov L, et al. Nanophthalmos: a review of the clinical spectrum and genetics[J/OL]. J Ophthalmol, 2018, 2018: 2735465[20180-05-09]. https://pubmed.ncbi.nlm.nih.gov/29862063/. DOI: 10.1155/2018/2735465.
8.	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
9.	Katoh M. Molecular cloning and characterization of MFRP, a novel gene encoding a membrane-type frizzled-related protein[J]. Biochem Biophys Res Commun, 2001, 282(1): 116-123. DOI: 10.1006/bbrc.2001.4551.
10.	Rong SS, Tang FY, Chu WK, et al. Genetic associations of primary angle-closure disease: a systematic review and meta-analysis[J]. Ophthalmology, 2016, 123(6): 1211-1221. DOI: 10.1016/j.ophtha.2015.12.027.
11.	Nowilaty SR, Khan AO, Aldahmesh MA, et al. Biometric and molecular characterization of clinically diagnosed posterior microphthalmos[J]. Am J Ophthalmol, 2013, 155(2): 361-372. DOI: 10.1016/j.ajo.2012.08.016.
12.	Aldahmesh MA, Nowilaty SR, Alzahrani F, et al. Posterior microphthalmos as a genetically heterogeneous condition that can be allelic to nanophthalmos[J]. Arch Ophthalmol, 2011, 129(6): 805-807. DOI: 10.1001/archophthalmol.2011.129.
13.	Khan AO. Posterior microphthalmos versus nanophthalmos[J/OL]. Ophthalmic Genet, 2008, 29(4): 189[2009-07-08]. https://pubmed.ncbi.nlm.nih.gov/19005993/. DOI: 10.1080/13816810802258862.
14.	Kameya S, Hawes NL, Chang B, et al. MFRP, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6[J]. Hum Mol Genet, 2002, 11(16): 1879-1886. DOI: 10.1093/hmg/11.16.1879.
15.	Mukhopadhyay R, Sergouniotis PI, Mackay DS, et al. A detailed phenotypic assessment of individuals affected by MFRP-related oculopathy[J]. Mol Vis, 2010, 16: 540-548.
16.	Wasmann RA, Wassink-Ruiter JS, Sundin OH, et al. Novel membrane frizzled-related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds[J]. Acta Ophthalmol, 2014, 92(3): 276-281. DOI: 10.1111/aos.12105.
17.	Matsushita I, Kondo H, Tawara A. Novel compound heterozygous mutations in the MFRP gene in a Japanese patient with posterior microphthalmos[J]. Jpn J Ophthalmol, 2012, 56(4): 396-400. DOI: 10.1007/s10384-012-0145-4.
18.	Lang E, Koller S, Atac D, et al. Genotype-phenotype spectrum in isolated and syndromic nanophthalmos[J]. Acta Ophthalmol, 2021, 99(4): e594-e607. DOI: 10.1111/aos.14615.
19.	Sundin OH, Leppert GS, Silva ED, et al. Extreme hyperopia is the result of null mutations in MFRP, which encodes a Frizzled-related protein[J]. Proc Natl Acad Sci USA, 2005, 102(27): 9553-9558. DOI: 10.1073/pnas.0501451102.
20.	Zenteno JC, Buentello-Volante B, Quiroz-González MA, et al. Compound heterozygosity for a novel and a recurrent MFRP gene mutation in a family with the nanophthalmos-retinitis pigmentosa complex[J]. Mol Vis, 2009, 15: 1794-1798.
21.	Almoallem B, Arno G, De Zaeytijd J, et al. The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56[J/OL]. Sci Rep, 2020, 10(1): 1289[2020-01-28]. https://pubmed.ncbi.nlm.nih.gov/31992737/. DOI: 10.1038/s41598-019-57338-2.
22.	Xu Y, Guan L, Xiao X, et al. Identification of MFRP mutations in Chinese families with high hyperopia[J]. Optom Vis Sci, 2016, 93(1): 19-26. DOI: 10.1097/OPX.0000000000000751.
23.	Wang J, Zhang VW, Feng Y, et al. Dependable and efficient clinical utility of target capture-based deep sequencing in molecular diagnosis of retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 2014, 55(10): 6213-6223. DOI: 10.1167/iovs.14-14936.
24.	Dinculescu A, Estreicher J, Zenteno JC, et al. Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept[J]. Hum Gene Ther, 2012, 23(4): 367-376. DOI: 10.1089/hum.2011.169.
25.	Godinho G, Madeira C, Grangeia A, et al. A novel MFRP gene variant in a family with posterior microphthalmos, retinitis pigmentosa, foveoschisis, and foveal hypoplasia[J]. Ophthalmic Genet, 2020, 41(5): 474-479. DOI: 10.1080/13816810.2020.1795888.
26.	Ayala-Ramirez R, Graue-Wiechers F, Robredo V, et al. A new autosomal recessive syndrome consisting of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disc drusen is caused by a MFRP gene mutation[J]. Mol Vis, 2006, 12: 1483-1489.

1. Ghose S, Sachdev MS, Kumar H. Bilateral nanophthalmos, pigmentary retinal dystrophy, and angle closure glaucoma-a new syndrome?[J]. Br J Ophthalmol, 1985, 69(8): 624-628. DOI: 10.1136/bjo.69.8.624.
2. Altintaş AK, Acar MA, Yalvaç IS, et al. Autosomal recessive nanophthalmos[J]. Acta Ophthalmol Scand, 1997, 75(3): 325-328. DOI: 10.1111/j.1600-0420.1997.tb00788.x.
3. Källén B, Tornqvist K. The epidemiology of anophthalmia and microphthalmia in Sweden[J]. Eur J Epidemiol, 2005, 20(4): 345-350. DOI: 10.1007/s10654-004-6880-1.
4. Hornby SJ, Xiao Y, Gilbert CE, et al. Causes of childhood blindness in the People's Republic of China: results from 1131 blind school students in 18 provinces[J]. Br J Ophthalmol, 1999, 83(8): 929-932. DOI: 10.1136/bjo.83.8.929.
5. Prasov L, Guan B, Ullah E, et al. Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort[J/OL]. Sci Rep, 2020, 10(1): 19986[2020-11-17]. https://pubmed.ncbi.nlm.nih.gov/33203948/. DOI: 10.1038/s41598-020-76725-8.
6. Won J, Smith RS, Peachey NS, et al. Membrane frizzled-related protein is necessary for the normal development and maintenance of photoreceptor outer segments[J]. Vis Neurosci, 2008, 25(4): 563-574. DOI: 10.1017/S0952523808080723.
7. Carricondo PC, Andrade T, Prasov L, et al. Nanophthalmos: a review of the clinical spectrum and genetics[J/OL]. J Ophthalmol, 2018, 2018: 2735465[20180-05-09]. https://pubmed.ncbi.nlm.nih.gov/29862063/. DOI: 10.1155/2018/2735465.
8. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
9. Katoh M. Molecular cloning and characterization of MFRP, a novel gene encoding a membrane-type frizzled-related protein[J]. Biochem Biophys Res Commun, 2001, 282(1): 116-123. DOI: 10.1006/bbrc.2001.4551.
10. Rong SS, Tang FY, Chu WK, et al. Genetic associations of primary angle-closure disease: a systematic review and meta-analysis[J]. Ophthalmology, 2016, 123(6): 1211-1221. DOI: 10.1016/j.ophtha.2015.12.027.
11. Nowilaty SR, Khan AO, Aldahmesh MA, et al. Biometric and molecular characterization of clinically diagnosed posterior microphthalmos[J]. Am J Ophthalmol, 2013, 155(2): 361-372. DOI: 10.1016/j.ajo.2012.08.016.
12. Aldahmesh MA, Nowilaty SR, Alzahrani F, et al. Posterior microphthalmos as a genetically heterogeneous condition that can be allelic to nanophthalmos[J]. Arch Ophthalmol, 2011, 129(6): 805-807. DOI: 10.1001/archophthalmol.2011.129.
13. Khan AO. Posterior microphthalmos versus nanophthalmos[J/OL]. Ophthalmic Genet, 2008, 29(4): 189[2009-07-08]. https://pubmed.ncbi.nlm.nih.gov/19005993/. DOI: 10.1080/13816810802258862.
14. Kameya S, Hawes NL, Chang B, et al. MFRP, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6[J]. Hum Mol Genet, 2002, 11(16): 1879-1886. DOI: 10.1093/hmg/11.16.1879.
15. Mukhopadhyay R, Sergouniotis PI, Mackay DS, et al. A detailed phenotypic assessment of individuals affected by MFRP-related oculopathy[J]. Mol Vis, 2010, 16: 540-548.
16. Wasmann RA, Wassink-Ruiter JS, Sundin OH, et al. Novel membrane frizzled-related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds[J]. Acta Ophthalmol, 2014, 92(3): 276-281. DOI: 10.1111/aos.12105.
17. Matsushita I, Kondo H, Tawara A. Novel compound heterozygous mutations in the MFRP gene in a Japanese patient with posterior microphthalmos[J]. Jpn J Ophthalmol, 2012, 56(4): 396-400. DOI: 10.1007/s10384-012-0145-4.
18. Lang E, Koller S, Atac D, et al. Genotype-phenotype spectrum in isolated and syndromic nanophthalmos[J]. Acta Ophthalmol, 2021, 99(4): e594-e607. DOI: 10.1111/aos.14615.
19. Sundin OH, Leppert GS, Silva ED, et al. Extreme hyperopia is the result of null mutations in MFRP, which encodes a Frizzled-related protein[J]. Proc Natl Acad Sci USA, 2005, 102(27): 9553-9558. DOI: 10.1073/pnas.0501451102.
20. Zenteno JC, Buentello-Volante B, Quiroz-González MA, et al. Compound heterozygosity for a novel and a recurrent MFRP gene mutation in a family with the nanophthalmos-retinitis pigmentosa complex[J]. Mol Vis, 2009, 15: 1794-1798.
21. Almoallem B, Arno G, De Zaeytijd J, et al. The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56[J/OL]. Sci Rep, 2020, 10(1): 1289[2020-01-28]. https://pubmed.ncbi.nlm.nih.gov/31992737/. DOI: 10.1038/s41598-019-57338-2.
22. Xu Y, Guan L, Xiao X, et al. Identification of MFRP mutations in Chinese families with high hyperopia[J]. Optom Vis Sci, 2016, 93(1): 19-26. DOI: 10.1097/OPX.0000000000000751.
23. Wang J, Zhang VW, Feng Y, et al. Dependable and efficient clinical utility of target capture-based deep sequencing in molecular diagnosis of retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 2014, 55(10): 6213-6223. DOI: 10.1167/iovs.14-14936.
24. Dinculescu A, Estreicher J, Zenteno JC, et al. Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept[J]. Hum Gene Ther, 2012, 23(4): 367-376. DOI: 10.1089/hum.2011.169.
25. Godinho G, Madeira C, Grangeia A, et al. A novel MFRP gene variant in a family with posterior microphthalmos, retinitis pigmentosa, foveoschisis, and foveal hypoplasia[J]. Ophthalmic Genet, 2020, 41(5): 474-479. DOI: 10.1080/13816810.2020.1795888.
26. Ayala-Ramirez R, Graue-Wiechers F, Robredo V, et al. A new autosomal recessive syndrome consisting of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disc drusen is caused by a MFRP gene mutation[J]. Mol Vis, 2006, 12: 1483-1489.

Chinese Journal of Ocular Fundus Diseases

Gene mutation detection of the posterior microphthalmia-retinal pigment degeneration family

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