Adam P DeLuca1,2, Wallace L M Alward1,2, Jeffrey Liebmann3, Robert Ritch4, Kazuhide Kawase5, Young H Kwon1,2, Alan L Robin6,7,8, Edwin M Stone1,2, Todd E Scheetz1,2, John H Fingert1,2. 1. Department of Ophthalmology and Visual Sciences, Carver College of Medicine. 2. Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA. 3. Bernard and Shirlee Brown Glaucoma Research Laboratory, Columbia University Medical Center. 4. Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mt. Sinai, New York, NY. 5. Department of Ophthalmology, Gifu University Graduate School of Medicine, Gifu, Japan. 6. Department of Ophthalmology, School of Medicine. 7. Department of International Health, and the Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD. 8. Department of Ophthalmology, University of Michigan, Ann Arbor, MI.
Abstract
BACKGROUND: Approximately 1% of normal tension glaucoma (NTG) cases are caused by TANK-binding kinase 1 (TBK1) gene duplications and triplications. However, the precise borders and orientation of these TBK1 gene copy number variations (CNVs) on chromosome 12 are unknown. METHODS: We determined the exact borders of TBK1 CNVs and the orientation of duplicated or triplicated DNA segments in 5 NTG patients with different TBK1 mutations using whole-genome sequencing. RESULTS: Tandemly duplicated chromosome segments spanning the TBK1 gene were detected in 4 NTG patients, each with unique borders. Four of 5 CNVs had borders located within interspersed repetitive DNA sequences (Alu and long interspersed nuclear element-L1 elements), suggesting that mismatched homologous recombinations likely generated these CNVs. A fifth NTG patient had a complex rearrangement including triplication of a chromosome segment spanning the TBK1 gene. CONCLUSIONS: No specific mutation hotspots for TBK1 CNVs were detected, however, interspersed repetitive sequences (ie, Alu elements) were identified at the borders of TBK1 CNVs, which suggest that mismatch of these elements during meiosis may be the mechanism that generated TBK1 gene dosage mutations.
BACKGROUND: Approximately 1% of normal tension glaucoma (NTG) cases are caused by TANK-binding kinase 1 (TBK1) gene duplications and triplications. However, the precise borders and orientation of these TBK1 gene copy number variations (CNVs) on chromosome 12 are unknown. METHODS: We determined the exact borders of TBK1 CNVs and the orientation of duplicated or triplicated DNA segments in 5 NTG patients with different TBK1 mutations using whole-genome sequencing. RESULTS: Tandemly duplicated chromosome segments spanning the TBK1 gene were detected in 4 NTG patients, each with unique borders. Four of 5 CNVs had borders located within interspersed repetitive DNA sequences (Alu and long interspersed nuclear element-L1 elements), suggesting that mismatched homologous recombinations likely generated these CNVs. A fifth NTG patient had a complex rearrangement including triplication of a chromosome segment spanning the TBK1 gene. CONCLUSIONS: No specific mutation hotspots for TBK1 CNVs were detected, however, interspersed repetitive sequences (ie, Alu elements) were identified at the borders of TBK1 CNVs, which suggest that mismatch of these elements during meiosis may be the mechanism that generated TBK1 gene dosage mutations.
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