title: Variants in ASB10 are associated with open-angle glaucoma.
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.affiliation: Institute of Human Genetics, University Hospital Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pasutto
authors.forename: Kate E
authors.initials: KE
authors.lastname: Keller
authors.forename: Nicole
authors.initials: N
authors.lastname: Weisschuh
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.forename: John R
authors.initials: JR
authors.lastname: Samples
authors.forename: Yong-Feng
authors.initials: YF
authors.lastname: Yang
authors.forename: Matthias
authors.initials: M
authors.lastname: Zenkel
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.forename: Christian Y
authors.initials: CY
authors.lastname: Mardin
authors.forename: Paolo
authors.initials: P
authors.lastname: Frezzotti
authors.forename: Beth
authors.initials: B
authors.lastname: Edmunds
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Kramer
authors.forename: Eugen
authors.initials: E
authors.lastname: Gramer
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Ted S
authors.initials: TS
authors.lastname: Acott
authors.forename: Mary K
authors.initials: MK
authors.lastname: Wirtz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D017089:Ankyrin Repeat; D001483:Base Sequence; D016022:Case-Control Studies; D002478:Cells, Cultured; D002924:Ciliary Body / Q000166:cytology / Q000378:metabolism; D005260:Female; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009924:Organ Culture Techniques; D010375:Pedigree; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014129:Trabecular Meshwork / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
chemical_list: C574092:ASB10 protein, human; D012333:RNA, Messenger; D050826:Suppressor of Cytokine Signaling Proteins