Mutated myocilin and heterozygous Sod2 deficiency act synergistically in a mouse model of open-angle glaucoma

Human Molecular Genetics
Myung Kuk JoeStanislav I Tomarev

Abstract

Glaucoma is a multifactorial optic neuropathy characterized by retinal ganglion cell (RGC) death and axonal degeneration leading to irreversible blindness. Mutations in the myocilin (MYOC) gene are the most common genetic factors of primary open-angle glaucoma. To develop a genetic mouse model induced by the synergistic interaction of mutated myocilin and another significant risk factor, oxidative stress, we produced double-mutant mice (Tg-MYOC(Y437H/+)/Sod2(+/-)) bearing human MYOC with a Y437H point mutation and a heterozygous deletion of the gene for the primary antioxidant enzyme, superoxide dismutase 2 (SOD2). Sod2 is broadly expressed in most tissues including the trabecular meshwork (TM) and heterozygous Sod2 knockout mice exhibit the reduced SOD2 activity and oxidative stress in all studied tissues. Accumulation of Y437H myocilin in the TM induced endoplasmic reticulum stress and led to a 45% loss of smooth muscle alpha-actin positive cells in the eye drainage structure of 10- to 12-month-old Tg-MYOC(Y437H/+)/Sod2(+/-) mice as compared with wild-type littermates. Tg-MYOC(Y437H/+)/Sod2(+/-) mice had higher intraocular pressure, lost about 37% of RGCs in the peripheral retina, and exhibited axonal degeneration in the reti...Continue Reading

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Citations

Aug 19, 2017·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Shaoqing HeThomas Yorio
Nov 30, 2018·International Journal of Molecular Medicine·Hongwei WangYong Ji
Jul 30, 2019·Current Eye Research·Karen EastlakeG Astrid Limb

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