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M Sarfarazi, T Rezaie, A Child, R Hitchings, G Brice, M Coca-Prados, E Héon, T Krupin, R RitchL Miller D Kreutzer and R P Crick; Adult-Onset Primary Open Angle Glaucoma Results From Mutations in Optineurin . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1936.
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Purpose: To identify the causative gene for adult-onset POAG (GLC1E) previously mapped by us to 10p14 region (AJHG 1998; 62:641-652). Methods: Candidate genes were screened for mutation by direct sequencing. Fifty-four POAG families consisting of 147 living affected subjects and at least one normal-tension glaucoma member were used for screening. Results: After excluding 4 candidates, mutations were found in a gene that we named Optineurin (OPTN). This gene has 16 exons (3 non-coding), encodes for 577 amino acids (66-kDa) and contains two putative bZIP transcription factor motifs, several leucine-zipper domains and a C2H2 type zinc finger. We found alternative splicing at 5-prime UTR that generated 3 isoforms (AF420371-3) but none altered the open reading frame. Two major transcripts of 2.0 and 3.6 kb were identified in both ocular and non-ocular tissues and the endogenous protein detected in HTM, NPCE and aqueous humors of human and 7 other species. Our immunocytochemistry study showed a perinuclear localization of endogenous protein that extended to Golgi complex and vesicles. We identified one truncating (g.691insAG) and 2 missense (E50K and R545Q) mutations in 9 families (16.67%) and another risk-associated change (M98K) in 23 (13.61%) of mainly LTG subjects. A recurrent mutation (E50K) results in significant reduction of optineurin protein in affected cultured cells. Cloning of the mouse gene revealed 584 amino acids (67 kDa) with 78% identity to OPTN, 13 coding exons and fully conserved boundaries. Conclusion: We identified optineurin as the first exclusive gene for adult-onset POAG. Optineurin interacts with a number of proteins to regulate apoptosis, inflammation and vasoconstriction and may have a neuroprotective role in glaucoma optic neuropathy.
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