A Cataract-Causing Mutation in the TRPM3 Cation Channel Disrupts Calcium Dynamics in the Lens.

TRPM3 belongs to the melastatin sub-family of transient receptor potential (TRPM) cation channels and has been shown to function as a steroid-activated, heat-sensitive calcium ion (Ca) channel. A missense substitution (p.I65M) in the TRPM3 gene of humans () and mice () has been shown to underlie an inherited form of early-onset, progressive cataract. Here, we model the pathogenetic effects of this cataract-causing mutation using 'knock-in' mutant mice and human cell lines. and its intron-hosted micro-RNA gene () were strongly co-expressed in the lens epithelium and other non-pigmented and pigmented ocular epithelia. Homozygous -mutant lenses displayed elevated cytosolic Ca levels and an imbalance of sodium (Na) and potassium (K) ions coupled with increased water content. Homozygous -mutant human lens epithelial (HLE-B3) cell lines and -mutant lenses exhibited increased levels of phosphorylated mitogen-activated protein kinase 1/extracellular signal-regulated kinase 2 (MAPK1/ERK2/p42) and MAPK3/ERK1/p44. Mutant TRPM3-M65 channels displayed an increased sensitivity to external Ca concentration and an altered dose response to pregnenolone sulfate (PS) activation. -mutant lenses shared the downregulation of genes involved in insulin/peptide secretion and the upregulation of genes involved in Ca dynamics. By contrast, -deficient lenses did not replicate the pathophysiological changes observed in -mutant lenses. Collectively, our data suggest that a cataract-causing substitution in the TRPM3 cation channel elicits a deleterious gain-of-function rather than a loss-of-function mechanism in the lens.