title: Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1.
abstract: Glaucoma is a leading cause of blindness in virtually every country. Development of an accurate diagnostic test for presymptomatic detection of individuals at risk is an urgent requisition for this condition. Herein, we report mapping of a new adult-onset primary open-angle glaucoma (POAG) locus on 5q22.1 (GLC1G) and identification of its defective gene. Mutation screening of seven candidate genes from the GLC1G critical region (approximately 2 Mb between D5S1466 and D5S2051) identified only one significant alteration in the WDR36 (WD40-repeat 36) gene. This mutation (i.e. D658G) was segregated in all affected members of our first GLC1G-linked family but it was absent in 476 normal control chromosomes. Further screening of WDR36 in a total of 130 POAG families revealed 24 DNA variations. Overall, four mutations (N355S, A449T, R529Q and D658G) were identified in 17 (5.02-6.92%) unrelated POAG subjects, 11 with high-pressure and six with low-pressure glaucoma. These mutations were absent in a minimum of 200 normal control chromosomes and, further they were conserved between WDR36 orthologues in mouse, rat, dog, chimp and human. WDR36 is a novel gene with 23 exons, which encodes for 951 amino acids and a protein with multiple G-beta WD40 repeats. By northern blotting, two distinct mRNA transcripts of 5.9 and 2.5 kb were observed in human heart, placenta, liver, skeletal muscle, kidney and pancreas. WDR36 gene expression in lens, iris, sclera, ciliary muscles, ciliary body, trabecular meshwork, retina and optic nerve were established by RT-PCR. In mouse, two transcripts of 3.5 and 2.9 kb showed analogous expression patterns to human. mRNA expressions were detected in 7-, 11-, 15- and 17-day-old developing mouse embryos. In summary, WDR36 is a novel causative gene for adult-onset POAG at the GLC1G locus. Specific ocular expressions and observed mutations are consistent with WDR36 role in etiology of both high- and low-pressure glaucoma.
authors.affiliation: Department of Surgery, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Sharareh
authors.initials: S
authors.lastname: Monemi
authors.forename: George
authors.initials: G
authors.lastname: Spaeth
authors.forename: Alexander
authors.initials: A
authors.lastname: DaSilva
authors.forename: Samuel
authors.initials: S
authors.lastname: Popinchalk
authors.forename: Elena
authors.initials: E
authors.lastname: Ilitchev
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Liebmann
authors.forename: Robert
authors.initials: R
authors.lastname: Ritch
authors.forename: Elise
authors.initials: E
authors.lastname: Héon
authors.forename: Ronald Pitts
authors.initials: RP
authors.lastname: Crick
authors.forename: Anne
authors.initials: A
authors.lastname: Child
authors.forename: Mansoor
authors.initials: M
authors.lastname: Sarfarazi
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D017354:Point Mutation; D040641:Quantitative Trait Loci
chemical_list: D005136:Eye Proteins; C502341:WDR36 protein, human