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Editors Selection IGR 18-1
Clinical Forms of Glaucoma: CNVs on chromosome 12q14 and NTG
Comment by Louis Pasquale & Bao Jian Fan on:
45924 Copy number variations on chromosome 12q14 in patients with normal tension glaucoma, Fingert JH; Robin AL; Stone JL et al., Human Molecular Genetics, 2011; 20: 2482-2494
Normal-tension glaucoma (NTG) is a genetically heterogeneous and complex disorder. While mutations in optineurin account for approximately 2% of patients with the disease, the genetic architecture of NTG remains largely unknown. Fingert et al. (788) report that copy number variations (CNVs) on chromosome 12q14 (GLC1P) are associated with NTG using linkage analysis. A large duplication within GLC1P segregates with the disease in an African-American family. Overlapping duplications are identified in another Caucasian family and an isolated patient with NTG, accounting for 1.3% (two out of 152) of unrelated Caucasian patients. Notably, these duplications are not detected in 326 patients with high-tension glaucoma, suggesting that they are specific to NTG. The authors propose that TANK-binding kinase-1 (TBK1) is the causative gene at GLC1P based on gene expression data. However, the data on TBK1 gene expression are somewhat disputable since the changes appear not to be statistically significant after correcting for multiple testing of hundreds of genetic loci (uncorrected p-value: 0.038, 0.045 and 0.00074 in cohort 1, 2 and the combined dataset, respectively). Nonetheless the TBK1 protein is a plausible biological candidate because it interacts with optineurin and this interaction is enhanced by a mutation (E50K) in optineurin. The authors hypothesize that duplications of TBK1 cause a dysregulation of NF- B signaling pathway, leading to apoptosis of retinal ganglion cells and the development of glaucoma. Overall, this study is the first to explore associations between CNVs and open-angle glaucoma. While further investigations are required to validate the role of TBK1 in the development of glaucoma, these findings are stimulating and open new avenues in exploring glaucoma pathogenesis.
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