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.

Objective: To compare the abilities of a new Glaucoma Probability Scoring (GPS) system and Moorfields regression analysis (MRA) to differentiate between glaucomatous and normal eyes using Heidelberg retinal tomograph (HRT)-III software and race-specific databases. Methods: In this prospective study, one eye (refractive error (5 D) each of consecutive normal patients and those with glaucoma was enrolled. All patients underwent a full eye examination, standard achromatic perimetry (Swedish Interactive Threshold Algorithm-standard automated perimetry (SITA-SAP), program 24-2) and confocal scanning laser ophthalmoscopy (HRT-II) within 1 month. Normal patients had two normal visual fields in both eyes (pattern standard deviation (PSD) .5% and Glaucoma Hemifield Test within 97% normal limits) and a normal clinical examination. Glaucoma was defined on the basis of SITA-SAP visual field loss (PSD,5% or Glaucoma Hemifield Test outside normal limits) on two consecutive visual fields. HRT-II examinations were exported to the HRT-III software (V.3.0), which uses an enlarged race-specific database, consisting of 733 eyes of white people and 215 eyes of black people. Race-adjusted MRA for the most abnormal sector (operator-dependent contour line placement) was compared with the global race-adjusted GPS (operator independent). MRA sectors outside the 99.9% confidence interval limits (outside normal limits) and GPS >0.64 were considered abnormal. Results: 136 normal patients (72 black and 64 white patients) and 84 patients with glaucoma (52 black and 32 white patients) were enrolled (mean age 50.4 (SD 14.4) years). The average visual field mean deviation was 20.4 (SD 1.1) db for the normal group and 27.3 (SD 6.7) db for the glaucoma group (p,0.001). Mean GPS values were 0.21 (SD 0.23) and 0.73 (SD 0.27) for normal and glaucomatous eyes, respectively (p,0.001). Sensitivity and specificity values were 77.1% and 90.3% for GPS, and 71.4% and 91.9% for MRA, respectively. Conclusions: In this cohort, GPS software sensitivity and specificity values are similar to those of MRA, which requires placement of an operator-dependent contour line. The development of software to detect glaucoma without a contour line is critical to improving the potential use of HRT as a tool for glaucoma detection and screening.

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