Pekka Vartiainen

Beautiful human genetics discovery of a missense variant in VE-PTP (aka PTPRB) that increases the risk of central serous chorioretinopathy (CSC) and varicose veins, but decreases risk of glaucoma. ​ VE-PTP encodes vascular endothelial-protein tyrosine phosphatase (removes phosphate), which is a natural inhibitor of tyrosine kinase receptors (adds phosphate) in vascular endothelial cells. ​ There is a huge literature on the vascular receptor tyrosine kinases (aka angiopoietin receptors), namely TIE1 and TIE2, that bind to its ligands angiopoietin 1 and 2 and regulate angiogenesis (en.wikipedia.org/wiki/Angiop…). ​ TIE2 (aka TEK) is specifically expressed in vascular endothelial cells. Researchers discovered VE-PTP in mice in 1999 by searching specifically for proteins with phosphatase activity that are bound to angiopoietin receptors in endothelial cells in the blood vessels of the brain (nature.com/articles/1202992). ​ Both TIE2 and VE-PTP are essential for blood vessel formation and patterning during embryo development, and so complete loss is incompatible with life. ​ The earliest human genetic discoveries related to TIE2 were from the early 1990s. Linkage analysis of large families with venous malformations pointed to a region in chromosome 9p. Soon it became apparent that the causative mutation was a gain of function missense mutation (pubmed.ncbi.nlm.nih.gov/8980…). ​ TIE2's link with glaucoma come from early mouse studies that showed, if you delete either TIE2 or its both ligands (Angpt1 and 2) during the late embryonic development, you bypass embryonic lethality, but the mice still develop severe glaucoma due to abnormal development schlemm's canal required for aqueous humor drainage in the eye (ncbi.nlm.nih.gov/pmc/article…) Later, human genetic confirmed this finding. Partial loss of TIE2 causes primary congenital glaucoma (ncbi.nlm.nih.gov/pmc/article…). ​ These discoveries formed the basis of development of VE-PTP inhibitors to activate TIE2 (as VE-PTP is a natural antagonist of TIE2) for the treatment of open angle glaucoma (tvst.arvojournals.org/articl…). ​ So far, no strong human genetic findings have surfaced for VE-PTP. Now, Rämö, Gorman, Weng, et al. report phenotypic consequences of a naturally occurring low-frequency missense variant that decreases VE-PTP function. ​ Fascinatingly, the phenotypic profile of partial loss of VE-PTP look inverse of the phenotypic profile of partial loss of TIE2. - While TIE2 deficiency causes glaucoma, VE-PTP deficiency protects against glaucoma. - While TIE2 over activation causes venous malformation, VE-PTP deficiency increases risk of varicose veins and serous chorioretinopathy (caused by increased fluid permeability of choroidal blood vessels resulting in fluid escaping to behind the retina and detachment). ​ Some interesting questions to answer: Are varicose veins and chorioretinopathy are merely developmental consequences of VE-PTP deficiency ? Will post-natal deletion of VE-PTP recapitulate these phenotypes in mice? This is important to know to assess adverse effects of VE-PTP inhibitors. ​ Similar to how VE-PTP inhibition is explored to treat open angle glaucoma, will TIE2 inhibition help treat chorioretinopathy? ​ Rämö, Gorman, Weng, et al. medRxiv 2024 medrxiv.org/content/10.1101/…