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L. Fernandez-Martinez, S. Letteboer, C. Y. Mardin, N. Weisschuh, B. H. Weber, B. Rautenstrauss, F. E. Kruse, A. Reis, R. Roepman, F. Pasutto; Heterozygous Rpgrip1 Mutations Are Associated With Primary Open-Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2168.
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Glaucoma is one of the major causes of blindness worldwide, comprising a heterogeneous group of neurodegenerative disorders. Primary open angle glaucoma (POAG), the predominant form of this disease, is inherited as a complex trait. Previous studies reported linkage for a POAG locus on chromosome 14q11. The Retinitis Pigmentosa GTPase Regulator-Interacting Protein 1 (RPGRIP1) gene maps to this region and is involved in different molecular processes affecting the physiology of the retina, a main target tissue in the pathology of glaucoma. The purpose of this project was to study a possible role of RPGRIP1 in the etiology of POAG.
Mutation screening was performed by direct resequencing. The functional effects of variants located within the RPGRIP1 C2 domains in the interaction with NPHP4 were assessed by monitoring reporter gene activation in a yeast two-hybrid system, including analysis of yeast growth under auxotrophic conditions and β-galactosidase activity determination, and by coimmunoprecipitation
Association of heterozygous RPGRIP1 variants with POAG was confirmed in two different large cohorts of patients from Germany and their respective control groups (p = 0.003, p = 0.013). Five of the mutations located in RPGRIP1 C2 domains impair the interaction between RPGRIP1 and NPHP4, suggesting that these are bona fide mutations.
Our findings suggest that rare heterozygous loss of function variants in RPGRIP1 are a risk factor for POAG, and a disrupt interaction of RPGRIP1 with different binding partners might be involved in the etiology of the disease. Therefore, our results reaffirm the hypothesis that genetic predisposition to POAG is mainly caused by rare variants rather than common SNPs.
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