Variants in ASB10 are associated with open-angle glaucoma

• DOI: 10.1093/hmg/ddr572
• Publication Date: 2011-12-09T04:31:53Z
• Authors: F. Pasutto; K. E. Keller; N. Weisschuh; H. Sticht; J. R. Samples; Y.-F. Yang; M. Zenkel; U. Schlotzer-Schr...; C. Y. Mardin; P. Frezzotti; B. Edmunds; P. L. Kramer; E. Gramer; A. Reis; T. S. Acott; M. K. Wirtz
• Keywords: Adult; Aged, 80 and over; Male; 570; Adolescent; Base Sequence; Ciliary Body; Molecular Sequence Data; Mutation, Missense; 610; Middle Aged; Ankyrin Repeat; Pedigree; 3. Good health; Alternative Splicing; 03 medical and health sciences; Organ Culture Techniques; 0302 clinical medicine; Case-Control Studies; Humans; Female; Amino Acid Sequence; Cells, Cultured; Glaucoma, Open-Angle; Aged

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.