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Editors Selection IGR 11-1
Genetics: Extracellular mutant protein
Comment by Doug Vollrath on:
22937 Heterozygous expression of myocilin glaucoma mutants increases secretion of the mutant forms and reduces extracellular processed myocilin, Aroca-Aguilar J-D; Sanchez-Sanchez F; Martinez-Redondo F et al., Molecular Vision, 2008; 14: 2097-2108
Myocilin glaucoma is a surprisingly prevalent inherited eye disease, accounting for 3-5% of open-angle glaucoma. The vast majority of individuals with myocilin glaucoma have one mutant and one normal copy of the gene. Mutant myocilin proteins are poorly secreted and are retained within cells. Co-expression of mutant and normal protein results in diminished secretion of the latter, probably due to formation of mixed myocilin oligomers. Aroca-Aguilar et al. (57) are the first to investigate the effect on mutant myocilin secretion of co-expression of normal protein. They found that expression of similar amounts of normal protein increases secretion of five mutant myocilins 1.5 to 5.4 fold, depending upon the specific mutant tested. Experimental replicates established the statistical significance of the results. The authors propose a new hypothesis for the pathogenesis of myocilin glaucoma, positing a key role for extracellular mutant protein in the disease.
Will blocking mutant myocilin secretion be of therapeutic benefit?They do not offer a specific mechanism linking extracellular mutant myocilin to glaucoma. Indeed, if such a mechanism exists, it is unlikely to be simply the amount of extracellular mutant protein because a mutant with a high level of secretion is associated with a milder glaucoma phenotype, whereas a mutant associated with an aggressive glaucoma phenotype is poorly secreted, even in the presence of normal protein. Thus, while the authors' efforts to more accurately model the heterozygous state of the disease are laudable, the validity of their speculation regarding a pivotal role for mutant extracellular protein in pathogenesis must be questioned. Understanding disease mechanisms is essential to development of rational therapy. The authors speculate that blocking mutant myocilin secretion may be of therapeutic benefit. This is in striking contrast to other work in the field, which indicates that increasing secretion of mutant myocilin will diminish the toxic effects on cells of intracellular, aggregated mutant protein.
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