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Editors Selection IGR 13-3

Basic Research: Reversing MYOC mutant phenotypes; a new potential treatment

Comment by Terete Borras on:

24011 Correction of the disease phenotype of myocilin-causing glaucoma by a natural osmolyte, Jia LY; Gong B; Pang CP et al., Investigative Ophthalmology and Visual Science, 2009; 50: 3743-3749

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It would be impossible not to get your head turned over the title of this publication: Correction of the disease phenotype of myocilincausing glaucoma by a natural osmolyte. However, even if correction of elevated IOP or glaucoma in patients or animals carrying myocilin mutations did not occur, Jia et al. (1137) were able to reverse the protein secretion and solubility deficiencies of a new myocilin (MYOC) mutant in cultured cells in vitro, which is not minor. The new mutation, D384N (AsparticAcid-384-Asparagine), was uncovered in a Chinese juvenileonset open-angle glaucoma family after sequencing the MYOC gene in 44 members. No disease-causing mutations were found in Optineurin, WDR36 and CYP1B1, the three other glaucomalinked genes. For their studies, wildtype and the D384N mutant cDNAs were cloned in an expression vector, transfected to immortalized trabecular meshwork cells and treated with the natural osmolyte trimethylamine N-oxide (TMAO). Because the vector contains two proteins tags, both myocilins are produced as fusion proteins and subsequently evaluated with antibodies to the tag, rather than to myocilin. Despite these technical shortcomings, it looks clear that treatment with 50 mM of TMAO for two days increased the secretion and solubility of the mutant. Further, it reduced the number of apoptotic cells caused by the mutant over expression. Ever since the discovery that a myocilin mutant was misfolded and not secreted (Caballero et al., 2000), investigators have attempted to reverse the secretion and solubility limitations of the MYOC mutants. Lowering the temperature of the cultures to 30°C, which facilitates protein folding, promoted secretion and reversed cell lethality (Liu, et al., 2004).

The concept of using chaperones for reversing MYOC mutant phenotypes appears to hold, and to be generic for different mutants

Likewise, the use of the chemical chaperone 4-PBA rescued four other mutant-myocilin-GFP fusion proteins in a previous study by the same authors. What is neat about this study is that TMAO is a natural molecule present in deepwater fish, where it protects the protein misfolding provoked by high hydrostatic pressure. What is relevant about this study is that the concept of using chaperones for reversing MYOC mutant phenotypes appears to hold, and to be generic for different mutants. If further confirmed by using nonfused proteins, primary cells and tissues, it could bring in the development of a new potential treatment for MYOC-caused glaucoma.

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