MYOC mutations were originally identified in patients with juvenile open angle glaucoma (JOAG). Cell culture and mouse studies suggest that MYOC mutations cause glaucoma through a dominant-negative effect on myocilin protein secretion. We tested this hypothesis with patient samples in this study. Glaucoma and control patients underwent complete ocular examination. DNA samples from glaucoma patients, unaffected relatives and controls were used for DNA sequencing of MYOC. Aqueous humor (AH) samples from glaucoma and control patients were obtained at the time of surgery. Myocilin protein in AH was detected by quantitative Western blot analysis. A de novo Val251Ala mutation of MYOC was found to segregate with disease in a family with autosomal dominant JOAG. Myocilin protein was detected in all control AH samples but was nearly undetectable in AH samples from a patient heterozygous for the Val251Ala mutation. Our results using human patient samples are consistent with a dominant-negative effect of pathogenic MYOC mutations on myocilin secretion.
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