Clinical and Genetic Analysis of Ser341Pro Variant in a Korean Family with Primary Open Angle Glaucoma

Overview

Journal Int J Ophthalmol

Specialty Ophthalmology

Date 2020 Nov 20

PMID 33214997

Citations 3

Authors

Sangwoo Moon

Namhee Kim

Jiwoong Lee

Affiliations

Soon will be listed here.

Abstract

Aim: To report the first discovery of Ser341Pro () variant in Korea and analyze its clinical characteristics and genetic significance.

Methods: Ten family members from three generations participated in this study and received the thorough ophthalmologic examination. Focused exome sequencing on a proband was performed to confirm the target mutations ( c.1021T>C) in the family members, and the direct sequencing was conducted. Variant was analyzed according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines.

Results: A nucleotide change from thymine to cytosine at c.1021T>C was found in eight family members. Three members diagnosed with primary open angle glaucoma (POAG) were characterized by severe clinical presentations, high intraocular pressure, and poor response to medical treatment (100% of the patient required filtering surgery). On variant analysis by ACMG/AMP guidelines, Ser341Pro is not found in normal population. Multiple computational predictive programs support a deleterious effect of Ser341Pro variant (PolyPhen 2, SIFT, Mutation Taster). Ser341Pro could be involved in moderate (PM) and supporting (PP) criteria (PM1, PM2, PP2, PP3). Combining the criteria, Ser341Pro has a combination of 2 moderate (PM1+PM2) and 2 supporting (PP2+PP3) criteria, which is interpreted to "likely pathogenic".

Conclusion: The Ser341Pro variant is correlated with severe phenotype of POAG. There are similar clinical aspects to previous studies: autosomal dominant inheritance, incomplete penetrance (62.50% and 66.67%), and proportion of patients requiring trabeculectomy (100% in both study). According to ACMG/AMP guidelines and the previous basic researches, the Ser341Pro variant had a "strong evidence of pathogenicity (PS3)" and then it could be interpreted to "pathogenic (PS3, PM1, PM2, PP2, PP3)". Additionally, Ser341Pro variant can be reported as "c.1021T>C (p.Ser341Pro), likely pathogenic, POAG, autosomal dominant" according to guideline.

Citing Articles

Improving the Yield of Genetic Diagnosis through Additional Genetic Panel Testing in Hereditary Ophthalmic Diseases.

Gwack J, Kim N, Park J Curr Issues Mol Biol. 2024; 46(5):5010-5022.

PMID: 38785568 PMC: 11119902. DOI: 10.3390/cimb46050300.

Molecular genetics of primary open-angle glaucoma.

Yadav M, Bhardwaj A, Yadav A, Dada R, Tanwar M Indian J Ophthalmol. 2023; 71(5):1739-1756.

PMID: 37203025 PMC: 10391438. DOI: 10.4103/IJO.IJO_2570_22.

Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data.

Scelsi H, Barlow B, Saccuzzo E, Lieberman R Hum Mutat. 2021; 42(8):903-946.

PMID: 34082484 PMC: 8295199. DOI: 10.1002/humu.24238.

References

Wei Y, Li Y, Bai Y, Wang M, Chen J, Ge J . Pro370Leu myocilin mutation in a Chinese pedigree with juvenile-onset open angle glaucoma. Mol Vis. 2011; 17:1449-56. PMC: 3110496. View

Nag A, Lu H, Arno M, Iglesias A, Bonnemaijer P, Broer L . Evaluation of the Myocilin Mutation Gln368Stop Demonstrates Reduced Penetrance for Glaucoma in European Populations. Ophthalmology. 2017; 124(4):547-553. DOI: 10.1016/j.ophtha.2016.11.018. View

Rose R, Karthikeyan M, Anandan B, Jayaraman G . Myocilin mutations among primary open angle glaucoma patients of Kanyakumari district, South India. Mol Vis. 2007; 13:497-503. PMC: 2649312. View

Wang F, Li Y, Lan L, Li B, Lin L, Lu X . Ser341Pro MYOC gene mutation in a family with primary open-angle glaucoma. Int J Mol Med. 2015; 35(5):1230-6. PMC: 4380197. DOI: 10.3892/ijmm.2015.2138. View

Fan B, Leung Y, Wang N, Lam S, Liu Y, Tam O . Genetic and environmental risk factors for primary open-angle glaucoma. Chin Med J (Engl). 2004; 117(5):706-10. View

Quigley H, Broman A . The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006; 90(3):262-7. PMC: 1856963. DOI: 10.1136/bjo.2005.081224. View

Huang X, Li M, Guo X, Li S, Xiao X, Jia X . Mutation analysis of seven known glaucoma-associated genes in Chinese patients with glaucoma. Invest Ophthalmol Vis Sci. 2014; 55(6):3594-602. DOI: 10.1167/iovs.14-13927. View

Somarajan B, Gupta S, Chaurasia A, Kumar S, Dutta P, Gupta V . The inheritance of juvenile onset primary open angle glaucoma. Clin Genet. 2016; 92(2):134-142. DOI: 10.1111/cge.12906. View

Qin L, Li J . [Investigation on the mutation of MYOC gene in two family pedigrees with primary open-angle glaucoma in Shanxi]. Yan Ke Xue Bao. 2007; 23(2):75-8. View

10.

Kee C, Ahn B . TIGR gene in primary open-angle glaucoma and steroid-induced glaucoma. Korean J Ophthalmol. 1998; 11(2):75-8. DOI: 10.3341/kjo.1997.11.2.75. View

11.

Borras T, Rowlette L, Tamm E, Gottanka J, Epstein D . Effects of elevated intraocular pressure on outflow facility and TIGR/MYOC expression in perfused human anterior segments. Invest Ophthalmol Vis Sci. 2002; 43(1):33-40. View

12.

Liuska P, Harju M, Kivela T, Turunen J . Prevalence of MYOC risk variants for glaucoma in different populations. Acta Ophthalmol. 2021; 99(7):e1090-e1097. DOI: 10.1111/aos.14738. View

13.

Xie X, Zhou X, Qu X, Wen J, Tian Y, Zheng F . Two novel myocilin mutations in a Chinese family with primary open-angle glaucoma. Mol Vis. 2008; 14:1666-72. PMC: 2530518. View

14.

Allen K, Gaier E, Wiggs J . Genetics of Primary Inherited Disorders of the Optic Nerve: Clinical Applications. Cold Spring Harb Perspect Med. 2015; 5(7):a017277. PMC: 4484958. DOI: 10.1101/cshperspect.a017277. View

15.

Park J, Kim M, Park C, Chae H, Lee S, Kim Y . Molecular analysis of myocilin and optineurin genes in Korean primary glaucoma patients. Mol Med Rep. 2016; 14(3):2439-48. PMC: 4991756. DOI: 10.3892/mmr.2016.5557. View

16.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . 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. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

17.

Wolfs R, Klaver C, Ramrattan R, van Duijn C, Hofman A, de Jong P . Genetic risk of primary open-angle glaucoma. Population-based familial aggregation study. Arch Ophthalmol. 1998; 116(12):1640-5. DOI: 10.1001/archopht.116.12.1640. View

18.

Avisar I, Lusky M, Robinson A, Shohat M, Dubois S, Raymond V . The novel Y371D myocilin mutation causes an aggressive form of juvenile open-angle glaucoma in a Caucasian family from the Middle-East. Mol Vis. 2009; 15:1945-50. PMC: 2751802. View

19.

McMonnies C . Glaucoma history and risk factors. J Optom. 2016; 10(2):71-78. PMC: 5383456. DOI: 10.1016/j.optom.2016.02.003. View

20.

Joe M, Sohn S, Hur W, Moon Y, Choi Y, Kee C . Accumulation of mutant myocilins in ER leads to ER stress and potential cytotoxicity in human trabecular meshwork cells. Biochem Biophys Res Commun. 2003; 312(3):592-600. DOI: 10.1016/j.bbrc.2003.10.162. View