Research Projects

Lens thickness (LT) is considered as a major quantitative trait that has reportedly been associated with multiple eye diseases including primary angle closure glaucoma (PACG), premature cataract, and myopia. To determine the genetic contribution of related loci, we conducted a genome-wide association study on lens thickness as the quantitative trait reflective of these disorders. Our findings suggest a novel genic area surrounding the PTPRM gene is associated at genome-wide significance level with increased lens thickness in Indian population (Chakraborty et al, Eur. J. Ophthalmol. 2023, in press). PTPRM is one of the family members of widely studied protein, tyrosine phosphatase. It has a similar structure to cell-cell adhesion molecules and has been reported to exhibit homophilic binding and possess the property to form cell-cell aggregates. It is found to bind with E-cadherin/alpha-catenin/beta-catenin complexes and importantly binds to the intracellular domain of E-cadherin controlling its phosphorylation and thus function. PTPRM, like other PTPs, is also tightly regulated by the balance between the actions of protein tyrosine kinases (PTKs) and PTPs. It is known that PTPRM is expressed in the developing brain and retina. In a study by Burden-Gulley et al. (J. Cell. Biol., 1999), the ability of embryonic chick retinal neurons to extend neurites on a PTPmu substrate was examined to promote neurite outgrowth from RGC neurons, and the migration of bipolar neurons and Müller glia from E8 mouse retinal explants. Meanwhile, PTPRM is shown to have an interaction at protein level with one of the crucial gap junction proteins connexin43 (Cx43). In summary, PTPRM regulates Cx43 levels in keratinocytes influencing gap junction regulation. Cx43 is associated with a more differentiated cell phenotype which explains its absence in these stem cell-enriched basal cell populations. While Cx43 and Cx50 are more abundant in the lens epithelial cells, the mature fiber region of the lens mostly has expression of Cx46 and Cx50. Cx43 level goes down from epithelial to differentiating fiber region to mature fiber region. Evidence indicated that Cx43 along with Cx50 surely has a crucial role in the differentiation of the lens fiber and maintaining the proper structure of the lens. Here we hypothesize, lens connexins play a crucial role in homeostasis of the lens. It would be worth looking at how these molecules and their interactions are influencing the quantitative trait lens thickness. There is sufficient evidence that suggests PTPRM and its interaction with connexin molecules, especially Cx43 having significant biological relevance in terms of determining the thickness of the lens. We would like to investigate the role of PTPRM in maintaining CX-43 mediated gap junctions in lens epithelium and its modulation upon differentiation and subsequently the role of PTPRM and CX-43 genetic interaction in lens development.