A pathologic MYOC mutation results in a novel skeletal muscle phenotype

MYOC is the gene with mutations most strongly associated with glaucoma. In the eye, MYOC transcripts are found within the trabecular meshwork, ciliary body, and retina. Other tissues with high MYOC transcript levels are skeletal muscle and heart. Despite intensive research efforts, the function of wild-type MYOC remains unknown and how mutant MYOC causes pathology is ambiguous. We hoped that by investigating mutant MYOC in a non-ocular tissue we would obtain novel insight into mutant MYOC pathology. For this study, we utilized a transgenic mouse with CMV-driven expression of cDNA encoding for a pathologic human MYOC Y437H mutant protein and we examined its skeletal muscle. Electron micrographs showed that sarcomeres in the skeletal muscle of mutant CMV-MYOC-Y437H mice had multiple M-bands. Western blots of soluble muscle lysates showed that there was a decrease in two M-band proteins, myomesin 1 (Myom1) and muscle creatine kinase (Ckm). Immunoprecipitation experiments identified CKM as a MYOC binding partner. We believe that binding of mutant MYOC to Ckm is changing sacromere M-band ultrastructure and we suggest that this may adversely impact normal muscle function. Subsequently, we speculate that a person with both a family history of glaucoma as well as a history of muscle ailments may potentially be carrying a MYOC gene mutation and physicians should be aware of this so as to enable early identification of individuals at high-risk for glaucoma