Copy Number Variations of TBK1 in Australian Patients With Primary Open-Angle Glaucoma

Abstract

PURPOSE To investigate the presence of TBK1 copy number variations in a large, well-characterized Australian cohort of patients with glaucoma comprising both normal-tension glaucoma and high-tension glaucoma cases. DESIGN A retrospective cohort study. METHODS DNA samples from patients with normal-tension glaucoma and high-tension glaucoma and unaffected controls were screened for TBK1 copy number variations using real-time quantitative polymerase chain reaction. Samples with additional copies of the TBK1 gene were further tested using custom comparative genomic hybridization arrays. RESULTS Four out of 334 normal-tension glaucoma cases (1.2%) were found to carry TBK1 copy number variations using quantitative polymerase chain reaction. One extra dose of the TBK1 gene (duplication) was detected in 3 normal-tension glaucoma patients, while 2 extra doses of the gene (triplication) were detected in a fourth normal-tension glaucoma patient. The results were further confirmed by custom comparative genomic hybridization arrays. Further, the TBK1 copy number variation segregated with normal-tension glaucoma in the family members of the probands, showing an autosomal dominant pattern of inheritance. No TBK1 copy number variations were detected in 1045 Australian patients with high-tension glaucoma or in 254 unaffected controls. CONCLUSION We report the presence of TBK1 copy number variations in our Australian normal-tension glaucoma cohort, including the first example of more than 1 extra copy of this gene in glaucoma patients (gene triplication). These results confirm TBK1 to be an important cause of normal-tension glaucoma, but do not suggest common involvement in high-tension glaucoma.

Partial duplication of the CRYBB1-CRYBA4 locus is associated with autosomal dominant congenital cataract

“…Ocular disease is no exception, with duplication or triplication of TBK1 in normal tension glaucoma being one example 18,19 , and a complex NHS triplication in the congenital cataract-associated Nance-Horan syndrome being another 20 . TBK1 CNVs associated with glaucoma cover the entire locus, so a mechanistic explanation has not been immediately obvious.…”

TBK1 duplication is found in normal tension and not in high tension glaucoma patients of Indian origin

“…Subsequently, screening a larger cohort for this region narrowed down the critical duplication interval to 300 kb which spanned three genes, namely TBK1, XPOT and RASSF3 (Fingert et al 2011;Kawase et al 2012). In addition to the African-American population, the duplication was found in NTG patients of Australian, Caucasian and Japanese ethnicities (Kawase et al 2012;Awadalla et al 2014;Ritch et al 2014). To detect the most likely candidate genes influenced by this duplication, a combination of three factors were considered, namely (i) expression in retinal ganglion cells; (ii) altered expression due to the duplication; and (iii) involvement with known glaucoma genes.…”

Association of Superoxide Dismutase 2 Polymorphism Rs4880 and Open-Angle Glaucoma in a Greek Patients’ Cohort

“…However, recent studies have identified new genetic variations that may contribute to POAG pathogenesis: among them, Caveolin 1 and 2 (CAV1, CAV2) on chromosome 7q31 [7]; tank binding kinase 1 (TBK1) [8,9], transmembrane and coiled-coil domains 1 (TMCO1) on chromosome 1q24 [10,11], S1 RNA binding domain 1 (SRBD1) [12], (CDKN2B-AS1) [11,13].…”