Interdependent regulation of trabecular meshwork cell physiology and intraocular pressure by KALRN and TMCO1

Abstract

Glaucoma is a leading cause of irreversible blindness. Primary open-angle glaucoma (POAG) is its most common form. Higher intraocular pressure (IOP), resulting from impaired aqueous humour outflow, is the cardinal mediating factor, and all proven treatments aim to lower IOP. POAG is a complex genetic disease with numerous loci linked to POAG and higher IOP. The mechanisms by which risk alleles cause disease remain unclear. Here, using primary trabecular meshwork (TM) cells, a cell type controlling outflow, and mice, we found that the POAG-associated gene KALRN encodes an endoplasmic reticulum (ER)-associated Rac regulator essential for TM homeostasis and normal IOP. KALRN loss caused widespread disruption from ER to calcium homeostasis and energy metabolism, leading to induction of cell senescence. KALRN-depletion also led to suppression of the ER translocase and calcium regulator TMCO1, encoded by a gene at one of the most significantly associated genomic loci for POAG. TMCO1-depletion in vitro and in vivo phenocopied KALRN-induced phenotypes, and reduced KALRN expression. These findings establish KALRN and TMCO1 as interdependent regulators of TM homeostasis and IOP, that link regulation of ER and intracellular calcium homeostasis to cell and tissue physiology, and illustrate how different genes linked to glaucoma can form regulatory pathways.