Optineurin Sequence Variants in British Glaucoma Subjects

Abstract

Abstract: : Purpose: A recent study reported the presence of Optineurin (OPTN) mutations in families with adult-onset normal tension glaucoma (NTG). The E50K mutation was identified in 13.5% of families, and a risk-associated change, M98K was identified in 13.6% of NTG subjects. The purpose of this study was to investigate the prevalence of these 2 OPTN sequence variants in a large cohort of unrelated British singleton glaucoma cases. Methods: Two-hundred and seventeen NTG, 183 high-tension glaucoma (HTG) and 95 control subjects were examined. Glaucoma patients had typical glaucomatous optic neuropathy with compatible visual field loss and open angles on gonioscopy. Those with NTG had untreated mean IOP on diurnal testing < 21 mm Hg, while HTG patients had IOP consistently >21 mm Hg. The E50K change was identified by bi-directional sequencing, while the M98K change was detected by the use of the restriction endonuclease, Stu I. Results: The prevalence of the E50K change was 3/217 (1.4%; 95% CI 0.3-4.0) in NTG subjects, 0/183 (0%; 95% CI 0-2) in HTG subjects and 0/95 (0%; 95% CI 0-3.8) among control subjects. The M98K variant was present in 24/217 (11.1%, 95%CI 7.2 - 16.0) NTG subjects compared to 8/183 (4.4%, 95%CI 1.9 - 8.4) HTG subjects (Χ ²= 6.8, p= 0.009, OR 2.9 [95% CI 1.3 to 6.6]) and 3/95 (3.2%, 95%CI 0.7 - 9.0) control subjects (Χ ²= 5.2, p= 0.02, OR 3.8 [95% CI 1.1 to 13.0]). Conclusions: Our data indicates that E50K is a significant but infrequent cause of sporadic NTG in the UK, and the association of M98K with NTG but not HTG suggests genetic heterogeneity between these 2 phenotypes. The ten-fold higher prevalence of E50K mutations in familial compared to sporadic NTG cases has important implications for the feasibility of genetic testing. Complete sequencing of the OPTN gene may reveal further mutations, and other differences between these groups.

Keywords: gene/expression • molecular biology • genetics