Variants in ASB10 are associated with open-angle glaucoma

Francesca Pasutto, Kate E. Keller, Nicole Weisschuh, Heinrich Sticht, John R. Samples, Yong Feng Yang, Matthias Zenkel, Ursula Schlötzer-Schrehardt, Christian Y. Mardin, Paolo Frezzotti, Beth Edmunds, Patricia L. Kramer, Eugen Gramer, André Reis, Ted S. Acott, Mary K. Wirtz

Research output: Contribution to journalArticle

50 Scopus citations

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 boxcontaining 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.

Original languageEnglish (US)
Article numberddr572
Pages (from-to)1336-1349
Number of pages14
JournalHuman molecular genetics
Volume21
Issue number6
DOIs
StatePublished - Mar 1 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Pasutto, F., Keller, K. E., Weisschuh, N., Sticht, H., Samples, J. R., Yang, Y. F., Zenkel, M., Schlötzer-Schrehardt, U., Mardin, C. Y., Frezzotti, P., Edmunds, B., Kramer, P. L., Gramer, E., Reis, A., Acott, T. S., & Wirtz, M. K. (2012). Variants in ASB10 are associated with open-angle glaucoma. Human molecular genetics, 21(6), 1336-1349. [ddr572]. https://doi.org/10.1093/hmg/ddr572