huMYOC-Y437H Mouse

The MYOC gene encodes a secreted glycoprotein known as myocilin, which is characterized by an N-terminal leucine zipper motif and a C-terminal olfactomedin-like domain ^[1]. Although myocilin is expressed in various tissues throughout the body—including skeletal muscle, heart, and the lining of the eye—it is most critically labeled and studied in the trabecular meshwork (TM) of the eye, where it is thought to play a role in cytoskeletal organization and cell-matrix interactions ^[2]. While the precise physiological function of myocilin remains a subject of ongoing research, mutations in the MYOC gene are the most common genetic cause of Primary Open-Angle Glaucoma (POAG) and Juvenile Open-Angle Glaucoma (JOAG). In these disease states, misfolded myocilin proteins fail to be secreted and instead accumulate within the endoplasmic reticulum of TM cells, leading to cellular stress, TM dysfunction, and a subsequent increase in intraocular pressure that can damage the optic nerve ^[3]. The Y437H mutation is one of the most severe and well-studied variants of the MYOC gene, involving a single nucleotide substitution that replaces the amino acid tyrosine with histidine at position 437. This specific mutation is strongly associated with Juvenile Open-Angle Glaucoma (JOAG), typically manifesting as an aggressive, early-onset form of the disease with exceptionally high intraocular pressure ^[4].

The huMYOC-Y437H mouse is a humanized model generated using gene-editing technology. It was created by replacing the mouse Myoc gene and its flanking upstream and downstream sequences with the corresponding human MYOC gene and flanking sequences, while introducing the p.Y437H (TAC to CAC) mutation into exon 3 of the human MYOC gene. This model is suitable for studying the pathogenic mechanisms of primary open-angle glaucoma (POAG) and juvenile open-angle glaucoma (JOAG), as well as for the screening, development, and preclinical evaluation of MYOC-targeted therapeutics.