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J. P. Vasconcellos, C. A. Braghini, A. Tavares, S. R. E. Pião Jr., G. P. Gil, V. P. Costa, M. B. Melo; New Mutation in the MYOC Gene, c.1187_1188insCCCAGA, Segregates with Juvenile Open Angle Glaucoma in a Brazilian Family. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3636.
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Mutations in the MYOC gene account for most cases of autosomal dominant juvenile open angle glaucoma (JOAG), an earlier and more severe form of primary open-angle glaucoma (POAG), as well as in approximately 3% of late onset POAG. Gain of function is the mechanism proposed to glaucoma development due to myocilin misfolding leading to the increase of intraocular pressure (IOP) caused by congestion of the trabecular meshwork secretory pathway. Missense mutations represent 85,9% of disease-causing variants while only 4,2% are small insertions. The purpose of this study was to evaluate the MYOC gene in a four generation family with JOAG.
A comprehensive ophthalmic examination was performed. POAG was defined as untreated IOP over 21 mmHg, with characteristic optic nerve and visual field glaucomatous damage. The MYOC gene coding regions and intron/exon boundaries were evaluated through direct sequencing.
A new mutation, c.1187_1188insCCCAGA, between the second and third bases of amino acid 396 was observed, segregating with the disease in four individuals from three generations and absent in 120 chromosomes from normal controls. This insertion leads to the inclusion of two amino acids, aspartic acid and proline, in the olfactomedin domain. Although it does not truncate the protein, according to secondary structure prediction programs, this mutation occurs just after a beta-sheet and within a casein kinase II phosphorylation motif.
The c.1187_1188insCCCAGA insertion is probably involved in JOAG etiology in this family. Its location, close to conserved regions among members of the OLF-domain family, predicted to be involved in the formation of beta-strands, might compromise the secondary structure and hence proper folding of the OLF-domain as well as myocilin affinity for its extracellular ligands. The secretion status of a previously described mutation, 396INS397 demonstrated that this variant remained sequestered within the two cell lines assayed. Functional studies should reveal if this mutation, as many others in the MYOC gene, impairs the secretion of normal myocilin.
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