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GWAS studies highlight three new genes linked to glaucoma, including PLEKHA7, a gene with a putative role in the barrier function of epithelial cells

In late 2012 research by an international consortium of scientists from Asia showed that three new genes appeared to associate with primary angle closure glaucoma (PACG), a significant cause of blindness worldwide. The original research, published in the journal Nature Genetics, reported a genome wide association study that included 3,771 PACG patients and 18,551 controls recruited across Singapore, Hong Kong, Malaysia, India and Vietnam. The authors of the research suggested that their findings might provide an improved understanding of the genetic mechanisms responsible for individual susceptibility to PACG. Follow up research on these findings has shown that one of the GWAS reported genes, PLEKHA7, appears to be expressed in the muscles, vascular endothelium, and epithelium of the iris, ciliary body and ciliary processes, trabecular meshwork (TM), and choroid. PLEKHA7 co-localization at these sites was seen with adherens junction markers (E-cadherin and beta-catenin) and tight junction markers (ZO-1), suggesting a potential role for PLEKHA7 in PACG via fluidic regulation.


Genome wide association studies or “GWAS”, aim to compare the genomic profiles of distinct population groups, in this case those with and without PACG. The methodology compares single nucleotide polymorphisms (SNPs) on a whole genome scale to uncover specific variants that associate with the presence or absence of disease. In the 2012 collaborative study led by Drs. Eranga N Vithana, Chiea-Chuen Khor, Ningli Wang and Tin Aung, the consortium reported significant associations at three new genetic loci: rs11024102 in the PLEKHA7 gene (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10^12); rs3753841 in the COL11A1 gene (per-allele OR = 1.20; P = 9.22 × 10^10) and, rs1015213, a region located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10^9).


One of these new players, the PLEKHA7 gene, (pleckstrin homology domain containing, family A member 7) is an interesting find as it is understood to code for a protein complex that regulates cellular permeability and therefore may play a role in abnormal fluid retention. Commenting on the significance of the original discovery, the authors of the GWAS report stated that PLEKHA7 may be “critical for the maintenance and stability of adherens junctions” and further explained that “in adult tissues, the adherens junctions maintain tissue homeostasis and, along with tight junctions, control epithelial and endothelial paracellular permeability. In the eye, tight junctions and adherens junctions have an essential role in structures of particular relevance to glaucoma, such as the ciliary body, iris, aqueous humor outflow system and choroid, by providing a barrier to fluid leakage”. The COL11A1 gene (encoding one of the two alpha chains of collagen, type XI) is expressed in the trabecular meshwork and so again represents a further smoking gun in respect of aqueous humor drainage. The third locus, between PCMTD1 (protein-L-isoaspartate (D-aspartate) O-methyltransferase domain containing 1) and ST18 (suppression of tumorigenicity 18, a zinc finger protein), is currently of unknown function.


New independent research work, published in 2014, has now shown PLEKHA7 to be part of a protein complex that stabilizes cell–cell junctions in epithelial and endothelial tissue. This protein complex is understood to be important in the assembly and disassembly of tight junctions (“TJ”, also known as zonulae occludentes) – key components in the establishment and maintenance of barriers between body compartments. Immuno-precipitation analysis has now demonstrated that PLEKHA7 forms a complex with the cytoplasmic TJ proteins ZO-1 and cingulin suggesting a putative role for PLEKHA7 in modulating the dynamics of assembly and disassembly of the TJ barrier via E-cadherin protein complex- and microtubule-dependent mechanisms. The recent findings by Serge Paschoud and colleagues at the University of Geneva, Switzerland (published in Tissue Barriers 2, e28755; April 2014) proposes that in cells that express specific forms of PLEKHA7, the increase in the amount of E-cadherin complex proteins and PLEKHA7 at the Tight Junctions “results in strengthened anchoring to the microtubule cytoskeleton, a more stable ZA (zonula adherens, cell–cell junctions in epithelial and endothelial tissues), and a less dynamic remodeling, delivery and endocytic removal of ZA proteins”. Clearly, any mutations negatively impacting on the faithful function of the PLEKHA7 gene product could compromise such function and, in the case of PACG, result in increased IOP.


The Swiss findings provide the first evidence for a role of PLEKHA7 in modulating the dynamics of the TJ barrier and may further our understanding of the molecular mechanisms through which PLEKHA7 participates in the pathogenesis of primary angle closure glaucoma and other disorders such as hypertension. The authors of the PLEKHA7 work conclude that, “PLEKHA7 expression levels may influence the response of epithelial tissues to physiological or pathological stimuli that modulate the paracellular barrier. Similarly, mutations in the PLEKHA7 locus, which might affect the expression or interactions of PLEKHA7, could influence the barrier function of epithelial cells involved in these diseases, by interfering with the stabilizing role of the E-cadherin complex on the TJ barrier. In summary, our results show that expression of specific exogenous PLEKHA7 constructs affects the dynamics of assembly and disassembly of the epithelial TJ barrier, and indicate that the E-cadherin protein complex and microtubules are mechanistically implicated in this modulation. These observations provide a framework for future studies on PLEKHA7 function in normal and diseased tissues.”