Abstract
Glaucoma is a genetically heterogeneous disorder and is the second cause of blindness worldwide owing to the progressive degeneration of retinal ganglion neurons. Very few genes causing glaucoma were identified to this date. In this study, we screened 10 candidate genes of glaucoma between the D14S261 and D14S121 markers of chromosome 14q11, a critical region previously linked to primary open-angle glaucoma (POAG). Mutation analyses of two large cohorts of patients with POAG, normal tension glaucoma (NTG) and juvenile open-angle glaucoma (JOAG), and control subjects, found only association of non-synonymous heterozygous variants of the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) with POAG, NTG and JOAG. The 20 non-synonymous variants identified in RPGRIP1 were all distinct from variants causing photoreceptor dystrophies and were found throughout all but one domain (RPGR-interacting domain) of RPGRIP1. Among them, 14 missense variants clustered within or around the C2 domains of RPGRIP1. Yeast two-hybrid analyses of a subset of the missense mutations within the C2 domains of RPGRIP1 shows that five of them (p.R598Q, p.A635G, p.T806I, p.A837G and p.I838V) decrease the association of the C2 domains with nephrocystin-4 (NPHPH). When considering only these five confirmed C2-domain mutations, the association remains statistically significant (P=0.001). Altogether, the data support that heterozygous non-synonymous variants of RPGRIP1 may cause or increase the susceptibility to various forms of glaucoma and that among other factors, physical impairment of the interaction of RPGRIP1with different proteins may contribute to the pathogenesis of forms of glaucoma.
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Acknowledgements
We thank all patients and control individuals for their participation, Olga Zwenger for technical assistance and Juliane Niedzella for patients’ recruitment support. This study was supported by Grant SFB 539 from the German Research Foundation. PAF was supported by grants from the National Institutes of Health (GM083165, EY019492 and 2P30-EY005722). PAF is the Jules and Doris Stein Research to Prevent Blindness Professor.
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The URLs for data presented herein are as follows:
National Center for Biotechnology Information (NCBI), http://www.ncbi.nlm.nih.gov/
Genome Browser of the University of California Santa Cruz (UCSC), http://genome.ucsc.edu/cgi-bin/hgTracks (reference sequences ssed: NT_026437 and NM_020366 and NP_065099)
Ensembl Database (http://www.ensembl.org).
ClustalW, http://www.ebi.ac.uk/clustalw/
Online Mendelian Inheritance in Man (OMIM): http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM/.
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Fernández-Martínez, L., Letteboer, S., Mardin, C. et al. Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma. Eur J Hum Genet 19, 445–451 (2011). https://doi.org/10.1038/ejhg.2010.217
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DOI: https://doi.org/10.1038/ejhg.2010.217
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