Pathogenic gene screening in a family with juvenile open-angle glaucoma_West China Medical Journal

Authors：

LÜ Zhiqing ¹ , LI Wenman ^1,2 , YAN Naihong ¹ ,  LI Ni ¹

1. Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Ophthalmology, the Third People’s Hospital of Chengdu, Chengdu, Sichuan 610000, P. R. China;

Corresponding author：

LI Ni, Email: linieye@wchscu.cn

Keywords：

Juvenile open-angle glaucoma; whole-exome sequencing; MYOC gene; Thr377Arg mutation

DOI：

10.7507/1002-0179.202403062

Video：

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Objective To identify genes associated with juvenile open-angle glaucoma (JOAG) by screening for gene mutation loci and clinical phenotype analysis in a JOAG family. Methods In January 2021, an ophthalmic examination was performed on members of a family with JOAG. Whole-exome sequencing was done on the proband to look for pathogenic genes. Family members were validated using Sanger sequencing, and a long-term follow-up was conducted. Results Three generations of the family comprised eight individuals, including three patients with JOAG. All patients carried a missense mutation in the MYOC gene c.1130C>G (p.Thr377Arg), which showed autosomal dominant inheritance. Other unaffected family members were not found to have the mutation. Conclusion The c.1130C>G (p.Thr377Arg) mutation in the MYOC gene may be responsible for the pathogenesis of this JOAG family.

Citation： LÜ Zhiqing, LI Wenman, YAN Naihong, LI Ni. Pathogenic gene screening in a family with juvenile open-angle glaucoma. West China Medical Journal, 2024, 39(12): 1887-1892. doi: 10.7507/1002-0179.202403062 Copy

1.	Kang JM, Tanna AP. Glaucoma. Med Clin North Am, 2021, 105(3): 493-510.
2.	Tham YC, Li X, Wong TY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology, 2014, 121(11): 2081-2090.
3.	Jonas JB, Aung T, Bourne RR, et al. Glaucoma. Lancet, 2017, 390(10108): 2183-2193.
4.	Inoue K, Shiokawa M, Fujimoto T, et al. Effects of treatment with bimatoprost 0.03% for 3 years in patients with normal-tension glaucoma. Clin Ophthalmol, 2014, 8: 1179-1183.
5.	Bailey JNC, Gharahkhani P, Kang JH, et al. Testosterone pathway genetic polymorphisms in relation to primary open-angle glaucoma: an analysis in two large datasets. Invest Ophthalmol Vis Sci, 2018, 59(2): 629-636.
6.	Wang K, Gaitsch H, Poon H, et al. Classification of common human diseases derived from shared genetic and environmental determinants. Nat Genet, 2017, 49(9): 1319-1325.
7.	Allen KF, Gaier ED, Wiggs JL. Genetics of primary inherited disorders of the optic nerve: clinical applications. Cold Spring Harb Perspect Med, 2015, 5(7): a017277.
8.	Shah M, Bouhenni R, Benmerzouga I. Geographical variability in CYP1B1 mutations in primary congenital glaucoma. J Clin Med, 2022, 11(7): 2048.
9.	Souzeau E, Hayes M, Zhou T, et al. Occurrence of CYP1B1 mutations in juvenile open-angle glaucoma with advanced visual field loss. JAMA Ophthalmol, 2015, 133(7): 826-833.
10.	Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science, 2007, 317(5843): 1397-1400.
11.	Kennan AM, Mansergh FC, Fingert JH, et al. A novel Asp380Ala mutation in the GLC1A/myocilin gene in a family with juvenile onset primary open angle glaucoma. J Med Genet, 1998, 35(11): 957-960.
12.	Huang C, Xie L, Wu Z, et al. Detection of mutations in MYOC, OPTN, NTF4, WDR36 and CYP1B1 in Chinese juvenile onset open-angle glaucoma using exome sequencing. Sci Rep, 2018, 8(1): 4498.
13.	Yun H, Wang Y, Zhou Y, et al. Human stem cells home to and repair laser-damaged trabecular meshwork in a mouse model. Commun Biol, 2018, 1: 216.
14.	Atienzar-Aroca R, Ferre-Fernández JJ, Tevar A, et al. Transgenic overexpression of myocilin leads to variable ocular anterior segment and retinal alterations associated with extracellular matrix abnormalities in adult zebrafish. Int J Mol Sci, 2022, 23(17): 9989.
15.	Stone EM, Fingert JH, Alward WL, et al. Identification of a gene that causes primary open angle glaucoma. Science, 1997, 275(5300): 668-670.
16.	Stothert AR, Suntharalingam A, Huard DJ, et al. Exploiting the interaction between Grp94 and aggregated myocilin to treat glaucoma. Hum Mol Genet, 2014, 23(24): 6470-6480.
17.	Nag A, Lu H, Arno M, et al. Evaluation of the myocilin mutation Gln368Stop demonstrates reduced penetrance for glaucoma in European populations. Ophthalmology, 2017, 124(4): 547-553.
18.	Yao YH, Wang YQ, Fang WF, et al. A recurrent G367R mutation in MYOC associated with juvenile open angle glaucoma in a large Chinese family. Int J Ophthalmol, 2018, 11(3): 369-374.
19.	Resch ZT, Fautsch MP. Glaucoma-associated myocilin: a better understanding but much more to learn. Exp Eye Res, 2009, 88(4): 704-712.
20.	Svidnicki PV, Braghini CA, Costa VP, et al. Occurrence of MYOC and CYP1B1 variants in juvenile open angle glaucoma Brazilian patients. Ophthalmic Genet, 2018, 39(6): 717-724.
21.	Xie JJ, Zhang GW, Cui HY, et al. Penetrance of MYOC gene mutation in primary open-angle glaucoma: a systematic review and meta-analysis. Ophthalmic Genet, 2022, 43(2): 240-247.
22.	Lynch JM, Dolman AJ, Guo C, et al. Mutant myocilin impacts sarcomere ultrastructure in mouse gastrocnemius muscle. PLoS One, 2018, 13(11): e0206801.
23.	Tamm ER. Myocilin and glaucoma: facts and ideas. Prog Retin Eye Res, 2002, 21(4): 395-428.
24.	Yam GH, Gaplovska-Kysela K, Zuber C, et al. Aggregated myocilin induces russell bodies and causes apoptosis: implications for the pathogenesis of myocilin-caused primary open-angle glaucoma. Am J Pathol, 2007, 170(1): 100-109.
25.	Waryah AM, Narsani AK, Sheikh SA, et al. The novel heterozygous Thr377Arg MYOC mutation causes severe juvenile open angle glaucoma in a large Pakistani family. Gene, 2013, 528(2): 356-359.
26.	Vincent AL, Billingsley G, Buys Y, et al. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet, 2002, 70(2): 448-460.
27.	Mataftsi A, Achache F, Héon E, et al. MYOC mutation frequency in primary open-angle glaucoma patients from Western Switzerland. Ophthalmic Genet, 2001, 22(4): 225-231.
28.	张孝欢, 张丁丁, 黄璐琳, 等. 散发型原发性开角型青光眼 MYOC 基因的变异分析. 中华医学遗传学杂志, 2019, 36(7): 662-665.
29.	Hewitt AW, Mackey DA, Craig JE. Myocilin allele-specific glaucoma phenotype database. Hum Mutat, 2008, 29(2): 207-211.
30.	Hewitt AW, Samples JR, Allingham RR, et al. Investigation of founder effects for the Thr377Met myocilin mutation in glaucoma families from differing ethnic backgrounds. Mol Vis, 2007, 13: 487-492.

1. Kang JM, Tanna AP. Glaucoma. Med Clin North Am, 2021, 105(3): 493-510.
2. Tham YC, Li X, Wong TY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology, 2014, 121(11): 2081-2090.
3. Jonas JB, Aung T, Bourne RR, et al. Glaucoma. Lancet, 2017, 390(10108): 2183-2193.
4. Inoue K, Shiokawa M, Fujimoto T, et al. Effects of treatment with bimatoprost 0.03% for 3 years in patients with normal-tension glaucoma. Clin Ophthalmol, 2014, 8: 1179-1183.
5. Bailey JNC, Gharahkhani P, Kang JH, et al. Testosterone pathway genetic polymorphisms in relation to primary open-angle glaucoma: an analysis in two large datasets. Invest Ophthalmol Vis Sci, 2018, 59(2): 629-636.
6. Wang K, Gaitsch H, Poon H, et al. Classification of common human diseases derived from shared genetic and environmental determinants. Nat Genet, 2017, 49(9): 1319-1325.
7. Allen KF, Gaier ED, Wiggs JL. Genetics of primary inherited disorders of the optic nerve: clinical applications. Cold Spring Harb Perspect Med, 2015, 5(7): a017277.
8. Shah M, Bouhenni R, Benmerzouga I. Geographical variability in CYP1B1 mutations in primary congenital glaucoma. J Clin Med, 2022, 11(7): 2048.
9. Souzeau E, Hayes M, Zhou T, et al. Occurrence of CYP1B1 mutations in juvenile open-angle glaucoma with advanced visual field loss. JAMA Ophthalmol, 2015, 133(7): 826-833.
10. Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science, 2007, 317(5843): 1397-1400.
11. Kennan AM, Mansergh FC, Fingert JH, et al. A novel Asp380Ala mutation in the GLC1A/myocilin gene in a family with juvenile onset primary open angle glaucoma. J Med Genet, 1998, 35(11): 957-960.
12. Huang C, Xie L, Wu Z, et al. Detection of mutations in MYOC, OPTN, NTF4, WDR36 and CYP1B1 in Chinese juvenile onset open-angle glaucoma using exome sequencing. Sci Rep, 2018, 8(1): 4498.
13. Yun H, Wang Y, Zhou Y, et al. Human stem cells home to and repair laser-damaged trabecular meshwork in a mouse model. Commun Biol, 2018, 1: 216.
14. Atienzar-Aroca R, Ferre-Fernández JJ, Tevar A, et al. Transgenic overexpression of myocilin leads to variable ocular anterior segment and retinal alterations associated with extracellular matrix abnormalities in adult zebrafish. Int J Mol Sci, 2022, 23(17): 9989.
15. Stone EM, Fingert JH, Alward WL, et al. Identification of a gene that causes primary open angle glaucoma. Science, 1997, 275(5300): 668-670.
16. Stothert AR, Suntharalingam A, Huard DJ, et al. Exploiting the interaction between Grp94 and aggregated myocilin to treat glaucoma. Hum Mol Genet, 2014, 23(24): 6470-6480.
17. Nag A, Lu H, Arno M, et al. Evaluation of the myocilin mutation Gln368Stop demonstrates reduced penetrance for glaucoma in European populations. Ophthalmology, 2017, 124(4): 547-553.
18. Yao YH, Wang YQ, Fang WF, et al. A recurrent G367R mutation in MYOC associated with juvenile open angle glaucoma in a large Chinese family. Int J Ophthalmol, 2018, 11(3): 369-374.
19. Resch ZT, Fautsch MP. Glaucoma-associated myocilin: a better understanding but much more to learn. Exp Eye Res, 2009, 88(4): 704-712.
20. Svidnicki PV, Braghini CA, Costa VP, et al. Occurrence of MYOC and CYP1B1 variants in juvenile open angle glaucoma Brazilian patients. Ophthalmic Genet, 2018, 39(6): 717-724.
21. Xie JJ, Zhang GW, Cui HY, et al. Penetrance of MYOC gene mutation in primary open-angle glaucoma: a systematic review and meta-analysis. Ophthalmic Genet, 2022, 43(2): 240-247.
22. Lynch JM, Dolman AJ, Guo C, et al. Mutant myocilin impacts sarcomere ultrastructure in mouse gastrocnemius muscle. PLoS One, 2018, 13(11): e0206801.
23. Tamm ER. Myocilin and glaucoma: facts and ideas. Prog Retin Eye Res, 2002, 21(4): 395-428.
24. Yam GH, Gaplovska-Kysela K, Zuber C, et al. Aggregated myocilin induces russell bodies and causes apoptosis: implications for the pathogenesis of myocilin-caused primary open-angle glaucoma. Am J Pathol, 2007, 170(1): 100-109.
25. Waryah AM, Narsani AK, Sheikh SA, et al. The novel heterozygous Thr377Arg MYOC mutation causes severe juvenile open angle glaucoma in a large Pakistani family. Gene, 2013, 528(2): 356-359.
26. Vincent AL, Billingsley G, Buys Y, et al. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet, 2002, 70(2): 448-460.
27. Mataftsi A, Achache F, Héon E, et al. MYOC mutation frequency in primary open-angle glaucoma patients from Western Switzerland. Ophthalmic Genet, 2001, 22(4): 225-231.
28. 张孝欢, 张丁丁, 黄璐琳, 等. 散发型原发性开角型青光眼 MYOC 基因的变异分析. 中华医学遗传学杂志, 2019, 36(7): 662-665.
29. Hewitt AW, Mackey DA, Craig JE. Myocilin allele-specific glaucoma phenotype database. Hum Mutat, 2008, 29(2): 207-211.
30. Hewitt AW, Samples JR, Allingham RR, et al. Investigation of founder effects for the Thr377Met myocilin mutation in glaucoma families from differing ethnic backgrounds. Mol Vis, 2007, 13: 487-492.

West China Medical Journal

Pathogenic gene screening in a family with juvenile open-angle glaucoma

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