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M. Sarfarazi, S. Monemi, A.H. Child; Molecular Characterization of WDR36: A Newly Identified Adult–Onset Primary Open Angle Glaucoma (POAG) Gene on 5q22.1 . Invest. Ophthalmol. Vis. Sci. 2006;47(13):195.
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© ARVO (1962-2015); The Authors (2016-present)
WDR36 is a 105–kDa multi–tasking protein that contains a number of G–beta WD40 repeats. Recently, we identified WDR36 as a novel causative gene (HMG 14:725; 2005) for an Adult–Onset POAG locus (GLC1G) that we previously mapped to 5q (ARVO 2003–2005). Subsequently, 3 other groups by sequencing a total of 311 French–Canadian, 309 German and 130 North–American glaucoma subjects confirmed the role of WDR36 in POAG (ASHG 2005). So far, a total of 67 DNA variants have been reported in 4 different populations. Of these, 19 non–synonymous amino acid alterations are only observed in glaucoma subjects (n=34). Of the remaining 48 variations, 16 are in coding regions and 32 are intronic. The A449T mutation was identified in all of the 4 populations, while N355S and R529Q were observed in only 2 and 3 studies, respectively. For this study, we aimed to establish ocular expression of WDR36 mRNA and protein and to further screen 2 of its binding partners of MAX and transcription factor E2F6 for mutation in a group of POAG subjects.
Northern blotting, RT–PCR, immunohistochemistry and direct DNA sequencing were used in this study.
We established ocular and non–ocular expression of this gene and its homologue, Wdr36, in human and mouse, respectively. WDR36 gene expression was observed in Lens, Iris, Sclera, Ciliary Muscles, Ciliary Body, Trabecular Meshwork, Retina and Optic Nerve. Our preliminary data shows that WDR36 protein has a prominent expression in Retinal Ganglion Cells. This protein is predicted to participate in a number of biological processes and, therefore, identification of WDR36–binding partners and study of their encoding molecules may provide new insights for delineation and underlying molecular mechanisms of glaucoma. Recently, MAX and TF–E2F6 were reported as new WDR36–binding partners. Therefore, we screened the entire coding regions of these 2 genes in a group of unrelated British glaucoma families. Direct DNA sequencing of MAX in a group of POAG families revealed 7 intronic variations, including 3 novel SNPs, while screening of TF–E2F6 in another group of families only identified one known SNP.
WDR36 expresses in various ocular regions and mutations in this gene are responsible for 5–10% of glaucoma subjects. However, WDR36–binding partners of MAX and TF–E2F6 do not seem to be directly involved in the etiology of POAG subjects that were screened during our study. Supported by EY–009947 and M01RR–06192.
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