Variants in ASB10 are associated with open-angle glaucoma

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

Research output: Contribution to journalArticle

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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 2012

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Ankyrin Repeat
Retinal Ganglion Cells
Open Angle Glaucoma
Glaucoma
Suppressor of Cytokine Signaling Proteins
Trabecular Meshwork
Messenger RNA
Ciliary Body
Aqueous Humor
Organ Culture Techniques
Blindness
Sequence Analysis
Molecular Biology
Exons
Amino Acids
Genes
Proteins
Primary Open Angle Glaucoma
Cell Body

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Pasutto, F., Keller, K., Weisschuh, N., Sticht, H., Samples, J. R., Yang, Y. F., ... Wirtz, M. (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

Variants in ASB10 are associated with open-angle glaucoma. / Pasutto, Francesca; Keller, Kate; Weisschuh, Nicole; Sticht, Heinrich; Samples, John R.; Yang, Yong Feng; Zenkel, Matthias; Schlötzer-Schrehardt, Ursula; Mardin, Christian Y.; Frezzotti, Paolo; Edmunds, Lorna (Beth); Kramer, Patricia L.; Gramer, Eugen; Reis, André; Acott, Ted; Wirtz, Mary.

In: Human Molecular Genetics, Vol. 21, No. 6, ddr572, 03.2012, p. 1336-1349.

Research output: Contribution to journalArticle

Pasutto, F, Keller, K, Weisschuh, N, Sticht, H, Samples, JR, Yang, YF, Zenkel, M, Schlötzer-Schrehardt, U, Mardin, CY, Frezzotti, P, Edmunds, LB, Kramer, PL, Gramer, E, Reis, A, Acott, T & Wirtz, M 2012, 'Variants in ASB10 are associated with open-angle glaucoma', Human Molecular Genetics, vol. 21, no. 6, ddr572, pp. 1336-1349. https://doi.org/10.1093/hmg/ddr572
Pasutto F, Keller K, Weisschuh N, Sticht H, Samples JR, Yang YF et al. Variants in ASB10 are associated with open-angle glaucoma. Human Molecular Genetics. 2012 Mar;21(6):1336-1349. ddr572. https://doi.org/10.1093/hmg/ddr572
Pasutto, Francesca ; Keller, Kate ; Weisschuh, Nicole ; Sticht, Heinrich ; Samples, John R. ; Yang, Yong Feng ; Zenkel, Matthias ; Schlötzer-Schrehardt, Ursula ; Mardin, Christian Y. ; Frezzotti, Paolo ; Edmunds, Lorna (Beth) ; Kramer, Patricia L. ; Gramer, Eugen ; Reis, André ; Acott, Ted ; Wirtz, Mary. / Variants in ASB10 are associated with open-angle glaucoma. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 6. pp. 1336-1349.
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