Mutation of the TRPM3 cation channel underlies progressive cataract development and lens calcification associated with pro‐fibrotic and immune cell responses

摘要: Transient-receptor-potential cation channel, subfamily M, member 3 (TRPM3) serves as a polymodal calcium sensor in diverse mammalian cell-types. Mutation of the human TRPM3 gene has been linked with inherited forms early-onset cataract or without other eye abnormalities. Here, we have characterized ocular phenotypes germline "knock-in" mice that harbor cataract-associated isoleucine-to-methionine mutation (p.I65M) (Trpm3-mutant) compared "knock-out" functionally lack (Trpm3-null). Despite strong expression Trpm3 lens epithelial cells, neither heterozygous (Trpm3+/- ) nor homozygous (Trpm3-/- Trpm3-null developed cataract; however, latter exhibited mild impairment growth. In contrast, Trpm3-M/M mutants severe, progressive, anterior pyramid-like microphthalmia, whereas Trpm3-I/M and hemizygous Trpm3-M/- pyramidal delayed onset progression-consistent semi-dominant phenotype. Histochemical staining revealed abnormal accumulation phosphate-like deposits collagen fibrils Trpm3-mutant lenses immunoblotting detected increased αII-spectrin cleavage products consistent calpain hyper-activation. Immunofluorescent confocal microscopy mutant fiber cell membrane degeneration was accompanied by alpha-smooth muscle actin positive (α-SMA+ve) myofibroblast-like cells macrosialin (CD68+ve) macrophage-like cells. Collectively, our mouse model data support an disease association for humans suggest (1) deficiency impaired growth but not transparency (2) dysfunction resulted progressive calcification coupled pro-fibrotic immune responses.