Glaucoma 1, Open Angle, P

A number sign (#) is used with this entry because of evidence that adult-onset open angle glaucoma-1P (GLC1P) is caused by an approximately 300-kb duplication on chromosome 12q14 that includes 4 genes. The TBK1 gene (604834) is considered to be the most likely candidate for the disorder (see MOLECULAR GENETICS).

Description

Glaucomas are a group of common neurodegenerative diseases of the optic nerve and retinal ganglion cells, characterized by progressive cupping of the optic nerve head with resultant visual field loss. Elevated intraocular pressure (IOP) is a strong risk factor for glaucoma; however, glaucoma can occur at any IOP. The most common form of glaucoma in the US is primary open-angle glaucoma (POAG; see 137760). POAG that occurs with an IOP below an arbitrary threshold of 21 mm Hg is often termed 'normal tension glaucoma' (summary by Fingert et al., 2011).

For a discussion of genetic heterogeneity of primary open angle glaucoma, see 137760.

Clinical Features

Bennett et al. (1989) studied a family in which 8 members over 4 consecutive generations exhibited glaucomatous optic atrophy and visual field loss at normal or borderline intraocular pressure. The disease was detectable in early adulthood and progressed slowly throughout life. A child in the fifth generation had features suggesting that he was affected, but he was too young for diagnostic certainty. Postmortem examination of the eyes of 1 affected family member demonstrated glaucomatous optic atrophy with pronounced cupping of the optic nerve head, posterior bowing of the lamina scleralis, and an almost complete loss of retinal ganglion cells, whereas the trabecular meshwork, choroidal and optic nerve vasculature, retinal pigment epithelium, and photoreceptors were normal in appearance. In 2 patients, retinal folds were visible that radiated from the optic disc through the macula. Bennett et al. (1989) stated that the 3 Norwegian families segregating autosomal dominant low-tension glaucoma described by Sandvig (1961) and which the author designated 'pseudoglaucoma,' appeared to have the same or a similar condition to the family they studied.

Fingert et al. (2011) studied 10 affected individuals from a 4-generation African American pedigree segregating autosomal dominant normal tension glaucoma (NTG). The glaucoma in this pedigree was characterized by early onset of disease (mean age at diagnosis, 36 years), as well as thin central corneas and low intraocular pressure (IOP). Five of the 6 affected family members with extensive ophthalmologic records had a maximum IOP of 21 mm Hg or less and met criteria for a diagnosis of normal tension glaucoma, whereas 1 patient had a maximum IOP of 22 mm Hg.

Mapping

In affected individuals from a 4-generation African American pedigree with NTG who were negative for mutation in the known glaucoma genes MYOC (601652) and OPTN (602432) and did not show linkage to either of those loci, Fingert et al. (2011) performed genomewide linkage analysis and obtained a maximum genomewide lod score of 2.7 at theta = 0 on chromosome 12q14. All 10 affected family members shared at least 1 allele of 1,869 contiguous SNPs on 12q14, defining a 9.47-Mb locus between rs12227270 and rs7488555. The SNP-based linkage analysis was confirmed with short tandem repeat markers, with marker D12S359 producing the maximum lod score of 2.3.

Molecular Genetics

Fingert et al. (2011) performed copy number variation (CNV) analysis of microarray data from the genomewide linkage analysis of a 4-generation African American pedigree with NTG and identified a large duplication of approximately 600 kb within the linked interval on chromosome 12q14 in all 10 affected family members. The duplication was not found in the Database of Genomic Variants. The duplication spanned 4 genes, TBK1 (604834), XPOT (603180), RASSF3 (607019), and GNS (607664), all of which were shown to be expressed in retinal tissue; however, studies using patient fibroblasts showed that only TBK1 and GNS had significantly increased transcription. CNV analysis of SNPs from a cohort of 400 glaucoma patients, 74 of whom had normal tension glaucoma, 400 patients with age-related macular degeneration (see 603075), and 100 controls identified 2 NTG patients with 12q14 duplications that overlapped the duplication detected in the African American pedigree. One was a sporadic NTG patient with a maximum IOP of 20 mm Hg and a 300-kb duplication. The other patient, who had a 650-kb duplication, came from an NTG family previously described by Bennett et al. (1989); DNA was available from 3 additional affected members, who all carried the duplication, whereas it was not found in 3 unaffected family members. Analysis of 78 more NTG patients did not reveal any additional 12q14 duplications, suggesting that chromosome 12q14 duplication might play a role in 2 (approximately 1.3%) of 152 cases of NTG. Fingert et al. (2011) noted that TBK1 was the only gene that showed significant differential gene expression in microarray studies and was included within all 3 detected duplications; Northern blot analysis of RNA from patient fibroblasts showed that expression of TBK1 was 1.48-fold greater than in controls.

Using quantitative PCR, Kawase et al. (2012) analyzed 252 unrelated Japanese NTG patients who had open angle glaucoma and maximum untreated IOPs of 21 mm Hg or less, 202 Japanese controls, 29 NTG patients from North Carolina, and 28 NTG patients from New York. One (0.40%) of the 252 Japanese NTG probands had a 300-kb duplication, chr12:64,803,839-65,098,981 (GRCh37). This duplication encompassed the TBK1 gene as well as the XPOT and RASSF3 genes, and was similar in extent to the 300-kb duplication previously reported in a sporadic NTG patient by Fingert et al. (2011). No duplications were found in the other patients or controls.

Fingert et al. (2014) investigated the structure of the 12q14 duplication in a patient from the African American NTG family originally studied by Fingert et al. (2011). The karyotype was normal, and FISH analysis demonstrated that the duplicated DNA was organized as a tandem repeat on chromosome 12q14. Eyes from 5 donors were evaluated by immunohistochemistry, which revealed that of the 4 genes in or near the 12q14 duplication, only TBK1 had specific expression in human retinal ganglion cells and the retinal nerve fiber layer; expression of RASSF3 and XPOT was relatively uniform throughout the retina, and GNS was expressed in a pattern consistent with Muller cells. Fingert et al. (2014) concluded that TBK1 was the gene most likely to play a role in glaucoma pathogenesis.

Using real-time quantitative PCR, Awadalla et al. (2015) investigated CNVs on chromosome 12q14, including the TBK1 gene, in a large, well-characterized Australian cohort of patients with NTG or high tension glaucoma (HTG). Four (1.2%) of 334 NTG cases were found to carry novel CNVs that differed from but overlapped with those previously reported. The CNVs, which were duplications in 3 cases and a triplication in 1, were confirmed by custom comparative genomic hybridization arrays. The CNVs segregated with NTG in all 4 families, showing an autosomal dominant pattern of inheritance. No CNVs were detected in 1,045 Australian patients with HTG or in 254 unaffected controls.