A glaucoma locus, GLC1A, was identified previously on chromosome 1q. A gene within this locus (encoding the protein myocilin) subsequently was shown to harbor mutations in 2-4% of primary open angle glaucoma patients. A total of 1703 patients was screened from five different populations representing three racial groups. There were 1284 patients from primarily Caucasian populations in Iowa (727), Australia (390) and Canada (167). A group of 312 African American patients was from New York City and 107 Asian patients from Japan. Overall, 61 different myocilin sequence variations were identified. Of the 61 variations, 21 were judged to be probable disease-causing mutations. The number of probands found to harbor such mutations in each population was: Iowa 31/727 (4.3%), African Americans from New York City 8/312 (2.6%), Japan 3/107 (2.8%), Canada 5/167 (3.0%), Australia 11/390 (2.8%) and overall 58/1703 (3. 4%). Overall, 16 (76%) of 21 mutations were found in only one population. The most common mutation observed, Gln368Stop, was found in 27/1703 (1.6%) glaucoma probands and was found at least once in all groups except the Japanese. Studies of genetic markers flanking the myocilin gene suggest that most cases of the Gln368Stop mutations are descended from a common founder. Although the specific mutations found in each of the five populations were different, the overall frequency of myocilin mutations was similar ( approximately 2-4%) in all populations, suggesting that the increased rate of glaucoma in African Americans is not due to a higher prevalence of myocilin mutations.

"Early-onset glaucoma" refers to genetically heterogeneous conditions for which glaucoma manifests at age 5-40 years and for which only a small subset is molecularly characterized. We studied the role of MYOC, CYP1B1, and PITX2 in a population (n=60) affected with juvenile or early-onset glaucoma from the greater Toronto area. By a combination of single-strand conformation polymorphism and direct cycle sequencing, MYOC mutations were detected in 8 (13.3%) of the 60 individuals, CYP1B1 mutations were detected in 3 (5%) of the 60 individuals, and no PITX2 mutations were detected. The range of phenotypic expression associated with MYOC and CYP1B1 mutations was greater than expected. MYOC mutations included cases of juvenile glaucoma with or without pigmentary glaucoma and mixed-mechanism glaucoma. CYP1B1 mutations involved cases of juvenile open-angle glaucoma, as well as cases of congenital glaucoma. The study of a family with autosomal dominant glaucoma showed the segregation of both MYOC and CYP1B1 mutations with disease; however, in this family, the mean age at onset of carriers of the MYOC mutation alone was 51 years (range 48-64 years), whereas carriers of both the MYOC and CYP1B1 mutations had an average age at onset of 27 years (range 23-38 years) (P=.001). This work emphasizes the genetic heterogeneity of juvenile glaucoma and suggests, for the first time, that (1) congenital glaucoma and juvenile glaucoma are allelic variants and (2) the spectrum of expression of MYOC and CYP1B1 mutations is greater than expected. We also propose that CYP1B1 may act as a modifier of MYOC expression and that these two genes may interact through a common pathway.

The purpose ofthis study was to determine the mechanical response of the lamina cribrosa (LC) to elevated intraocular pressure (IOP) so as to identify possible mechanisms of optic nerve damage in early glaucoma. Ten In this paper, we seek to complement previous work by a direct morphometric study of the response of the LC in normal human eyes to acute changes in IOP. We feel that this approach has several advantages. Firstly, a morphometric approach allows both the overall shape and the internal architecture of the LC to be evaluated as a function of pressure. This is in contrast with previous studies of the effects of pressure on the LC which focused on positional changes of the anterior surface of the retina at the ONH or on the topography ofthe ONH. Secondly, the use of normal eyes in acute experiments permits potential assessment of the factors initiating axonal damage, since the effect of IOP on a presumably normal ONH can be studied. This is important since ONH architecture in glaucomatous eyes will be substantially different from that ofnormal eyes, owing to degenerative optic neuropathy.The goals of the present work were: (i) to characterise and quantify acute deformations of the LC as a result of elevated IOP; (ii) to formulate a mechanical model of the stress distribution within the LC which is consistent with clinically and experimentally observed patterns of axonal damage in glaucoma; and (iii) to identify features of the LC which might increase the susceptibility of some eyes to glaucomatous damage. The experimental approach was to fix normal human eyes at either high or low pressure and then to compare morphometrically the LC from the low and high pressure groups.Materials and methods Ten pairs of ostensibly normal human eyes (average age 69 years) from which the corneas had been removed for transplantation were obtained within 24 hours post mortem from the Eye Bank of Ontario. The eyes were hemisected at the equator and the vitreous was carefully removed under an operating microscope. This dissection was performed while suspending the eye in a saline bath to prevent the retina from detaching. Each posterior hemisphere was then mounted onto a plastic perfusion dish'4 which sealed it at the equator and allowed it to be pressurised. Briefly, this dish had a small discshaped elevated region with bevelled edges which effectively matched the inner diameter of the globe at the equator. The eye was then clamped in position by a ring whose inner