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Editors Selection IGR 14-3

Basic Reseach: Myocillin

Comment by Ernst Tamm on:

12150 Myocilin mutations causing glaucoma inhibit the intracellular endoproteolytic cleavage of myocilin between amino acids Arg²²⁶ and Ile²²⁷, Aroca-Aguilar JD; Sanchez-Sanchez F; Ghosh S et al., Journal of Biological Chemistry, 2005; 280: 21043-21051

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Aroca-Aguilar et al. (450) have studied the expression and processing of myocilin in immortalized cell lines, including some that were derived from ciliary body and iris. Mutations in myocilin cause autosomal-dominant juvenile glaucoma and a subset of adult-onset primary open-angle glaucoma. The cell lines were transfected to express wild-type myocilin, as well as myocilin containing pathogenic mutations. After transfection, wild-type myocilin was detected in the cell culture supernatant together with a 35 kDa fragment of myocilin containing its olfactomedin domain. After a careful characterization of this fragment, the authors could show that the fragment orginates from intracellular endoproteolytic processing and is co-secreted with non-processed myocilin. A protein of 35 kDa in length, which stained with similar antibodies was also found in samples of human aqueous humor, indicating that endoproteolytic processing of myocilin might also happen in vivo, although additional data are still needed to support this assumption. Corroborating the findings of a couple of other researchers, Aroca-Aguilar and co-workers found that mutated myocilin is not secreted from cultured cells, but retained in the rough endoplasmatic reticulum. Under these conditions, endoproteolytic processing could not be observed. This well done study provides a new puzzling aspect of myocilin, a molecule whose biochemical function is still unclear after years of research. Naturally, it remains difficult to judge, whether the findings are relevant for any functions of myocilin in the living eye. At least, direct effects of the 35 kDa fragment on aqueous outflow appear to be very unlikely, as Goldwich et al. (IOVS, 2003;44:1953-1961) showed previously that an olfactomedin fragment of myocilin with almost identical size, which was obtained and purified under very similar experimental conditions, did not effect outflow facility when added to human anterior segment-perfused organ cultures.

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