IMPORTANCE Normal-tension glaucoma (NTG) is definitely a common cause of vision

IMPORTANCE Normal-tension glaucoma (NTG) is definitely a common cause of vision loss. of another case of NTG attributed to gene duplication strengthens the case that this mutation causes glaucoma. The genetic basis of main open-angle glaucoma (POAG) is definitely complex. Recent large population-based studies possess identified numerous genetic factors related to POAG, including (OMIM 601652)12 or (OMIM 602432)13 can cause POAG with minimal influence from additional genes or environmental factors. Mutations in cause 3% to 4% of POAG instances worldwide.14 Individuals with is LEE011 IC50 associated with POAG that occurs at reduce IOP (ie, normal-tension glaucoma [NTG]).13 mutations have been linked to 1% to 2% of NTG instances.16,17 Overall, the known single-gene causes of POAG are responsible for approximately 5% of instances of POAG.11 More recently, a third glaucoma gene, gene. encodes a kinase protein that directly interacts with and phosphorylates OPTN,20,21 the protein encoded from the only additional known NTG gene.13 is the only gene LEE011 IC50 encompassed by all known chromosome 12q14 duplications in NTG individuals.18,19 Moreover, TBK1 is specifically indicated within the ocular tissue most affected by NTG, the retinal ganglion LEE011 IC50 cell coating, and duplication of the gene prospects to a significant increase in its transcription level.18 The sum of these data strongly suggest that duplication of causes 0.4% to 1 1.3% of NTG cases.18,19 However, animal and/or functional studies will be required to definitively demonstrate that chromosome 12q14 duplications cause NTG by altering the function of TBK1 rather than through effects on additional neighboring genes. The finding that is a glaucoma gene suggests biological pathways that may be important in the pathogenesis of NTG. Both known NTG genes, and gene duplications in NTG individuals lead to improved transcription of messenger RNA,18 which may lead to retinal ganglion cell death by activation of autophagy or altering NF-B signaling. With this statement, we investigated the part of gene duplication in 3 additional NTG patient populations to further explore the part of the gene in NTG. METHODS All participants offered written educated consent, and study was conducted with the approval of the institutional review table of the University or college of Iowa. All participants were examined by a fellowship-trained glaucoma professional. Criteria for analysis of NTG included standard glaucomatous optic nerve damage and visual field loss having a maximum recorded IOP of 21 mm Hg or less, as previously described.15,18,19 Three cohorts of individuals and controls were enrolled from Southampton, United Kingdom (180 individuals and 178 controls), Rochester, Minnesota (65 individuals and 12 controls), and New York, New York (96 individuals and 16 controls). An additional 208 settings from Iowa were also enrolled. None of the individuals or settings in the current statement were included in earlier studies of gene duplications using a B2m quantitative polymerase chain reaction assay (TaqMan Quantity Assay; Applied Biosystems) as previously explained.18,19 Positive quantitative polymerase chain reaction results were confirmed, and duplication borders were defined with comparative genome hybridization (CGH) using whole genome microarrays (NimbleGen 720 000 microarray; Roche NimbleGen) following a manufacturers protocol. The borders and degree of recognized gene duplications were compared with previously reported gene duplications in additional NTG individuals using the current build of the human being genome (hg19).18,19 RESULTS A total of 755 participants from 3 populations (Southampton, United Kingdom; Rochester, Minnesota; and New York, New York) were tested for duplication of the gene using a quantitative polymerase chain reaction assay. A gene duplication was recognized in 1 (patient GGR-590-1) of 96 individuals (1.0%) from New York. No gene duplication was recognized in any of the settings or in the additional NTG cohorts. The degree of the chromosome 12q14 duplication in individual GGR-590-1 was determined by examination having a CGH microarray. The duplication encompasses 370 kilobase pairs (kbp), stretches LEE011 IC50 from 64 563 to 64 933 kbp, and spans the gene and part of the gene (Number 1). Number 1 gene duplications Case Statement Patient GGR-590-1 is definitely a 65-year-old white female who was diagnosed as having NTG at 47 years of age with maximum recorded IOP of 16 mm Hg in both eyes, progressive visual field damage (left eye greater than right attention), and glaucomatous cup-to-disc ratios. As part of her evaluation,.