title: Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma.
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.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Lorena
authors.initials: L
authors.lastname: Fernández-Martínez
authors.forename: Stef
authors.initials: S
authors.lastname: Letteboer
authors.forename: Christian Y
authors.initials: CY
authors.lastname: Mardin
authors.forename: Nicole
authors.initials: N
authors.lastname: Weisschuh
authors.forename: Eugen
authors.initials: E
authors.lastname: Gramer
authors.forename: Bernhard Hf
authors.initials: BH
authors.lastname: Weber
authors.forename: Bernd
authors.initials: B
authors.lastname: Rautenstrauss
authors.forename: Paulo A
authors.initials: PA
authors.lastname: Ferreira
authors.forename: Friedrich E
authors.initials: FE
authors.lastname: Kruse
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.forename: Francesca
authors.initials: F
authors.lastname: Pasutto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001766:Blindness / Q000235:genetics; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007429:Intraocular Pressure; D057066:Low Tension Glaucoma / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011506:Proteins / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics; D012307:Risk Factors; D055815:Young Adult
chemical_list: D003598:Cytoskeletal Proteins; D011506:Proteins; C415903:RPGRIP1 protein, human