Variants in ASB10 are associated with open-angle glaucoma

Pasutto F, Keller KE, Weisschuh N, Sticht H, Samples JR, Yang YF, Zenkel M, Schlötzer-Schrehardt U, Mardin CY, Frezzotti P, Edmunds B, Kramer PL, Gramer E, Reis A, Acott TS, Wirtz MK (2012)

Publication Type: Journal article

Publication year: 2012

Journal

Human Molecular Genetics Oxford University Press (OUP): Policy B - Oxford Open Option B

Book Volume: 21

Pages Range: 1336-49

Journal Issue: 6

DOI: 10.1093/hmg/ddr572

Abstract

The molecular events responsible for obstruction of aqueous humor outflow and the loss of retinal ganglion cells in glaucoma, one of the main causes of blindness worldwide, remain poorly understood. We identified a synonymous variant, c.765C>T (Thr255Thr), in ankyrin repeats and suppressor of cytokine signaling box-containing protein 10 (ASB10) in a large family with primary open angle glaucoma (POAG) mapping to the GLC1F locus. This variant affects an exon splice enhancer site and alters mRNA splicing in lymphoblasts of affected family members. Systematic sequence analysis in two POAG patient groups (195 US and 977 German) and their respective controls (85 and 376) lead to the identification of 26 amino acid changes in 70 patients (70 of 1172; 6.0%) compared with 9 in 13 controls (13 of 461; 2.8%; P = 0.008). Molecular modeling suggests that these missense variants change ASB10 net charge or destabilize ankyrin repeats. ASB10 mRNA and protein were found to be strongly expressed in trabecular meshwork, retinal ganglion cells and ciliary body. Silencing of ASB10 transcripts in perfused anterior segment organ culture reduced outflow facility by ~50% compared with control-infected anterior segments (P = 0.02). In conclusion, genetic and molecular analyses provide evidence for ASB10 as a glaucoma-causing gene.

Authors with CRIS profile

Heinrich Sticht Professur für Bioinformatik Matthias Zenkel Department of Ophthalmology Ursula Schlötzer-Schrehardt Medizinische Fakultät Christian Mardin Department of Ophthalmology André Wiesmann da Silva Reis Lehrstuhl für Humangenetik

Involved external institutions

Oregon Health and Science University (OSHU) US United States (USA) (US) Universitätsklinikum Tübingen DE Germany (DE) Università degli Studi di Siena (UNISI) / University of Siena IT Italy (IT) Universitätsklinikum Würzburg DE Germany (DE)

How to cite

APA:

Pasutto, F., Keller, K.E., Weisschuh, N., Sticht, H., Samples, J.R., Yang, Y.-F.,... Wirtz, M.K. (2012). Variants in ASB10 are associated with open-angle glaucoma. Human Molecular Genetics, 21(6), 1336-49. https://doi.org/10.1093/hmg/ddr572

MLA:

Pasutto, Francesca, et al. "Variants in ASB10 are associated with open-angle glaucoma." Human Molecular Genetics 21.6 (2012): 1336-49.

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