Invited Symposium: Glaucoma: Diagnosis and Therapy
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Introduction
Glaucoma, a major cause of blindness, is characterized by cupping of the optic nerve head with subsequent retinal nerve fiber loss, usually associated with elevated intraocular pressure. Primary open angle glaucoma (POAG) is an autosomal dominantly inherited, heterogeneous disease. In Germany the incidence of blindness due to glaucoma is estimated in about 40.000 individuals. The molecular mechanisms of POAG are still unknown. Up to now different loci were identified: GLC1A, GLC1B, GLC1C, GLC1D, GLC1E, GLC1E, GLC1F. For juvenile open angle glaucoma (JOAG) a genetic locus (GLC1A) was identified on chromosome 1q21-q31 (1) by linkage analysis and finally refined to 1q24.3-q25.2 (2). Meanwhile several GLC1A mutations were identified in the trabecular meshwork inducible glucocorticoid response (TIGR) gene, synonymous Myocilin (MYOC), in familial as well as sporadic cases of early- and late-onset types of open angle glaucoma (2,3,4,5,6,7). Most of them are focused in exon 3 encoding a evolutionarily conserved olfactomedin homologous domain.
Materials and Methods
POAG patients were routinely examined by Slit-lamp biomicroscopy, gonioscopy, perimetry, Goldmann applanation tonometry and morphometry of the optic disc. 10 to 15 ml of EDTA-blood was used for DNA extraction. SSCP analysis and subsequent sequence analysis was performed as described in (2).
Results
We performed a GLC1A gene mutation screening in a group of 400 cases of POAG, including familiar cases and unselected, clinically sporadic cases. In 6 families and 10 sporadic cases an aberrant SSCP pattern was found. Sequence analysis revealed different potentially pathogenic mutations: Pro370Leu, Gly367Arg, Gln368Stop, Gly434Ser, Asn450Asp, Arg470Cys. In 8 other families no mutations were found up to now. Furthermore twice a Tyr347Tyr polymorphism and once a Thr325Thr polymorphism were found. The heterocygote Gln368Stop mutation was found in 6 unrelated cases. One of the patients with the Gln368Stop mutation has normal intraocular pressure (IOP) values, whereas two others have an increased IOP. 5 from 18 analysed healthy family members of family W.T. are carriers of the Gln368Stop mutation, whereas 6 analysed healthy family members of family W.F.-R. are not. As different groups reported this Gln368Stop mutation in several healthy individuals (3,5,6), it is unlikely that it works pathogenic in a direct manner.
Discussion and Conclusion
Our data suggests that TIGR/MYOC plays a crucial, yet unknown, role in POAG pathogenesis. However, the fact that the Gln368Stop mutation was found as well in healthy carriers shows that a more complex pathomechanism seems to be involved in POAG.
References
1. Sheffield et al. (1993) Nat Genet 4:47-502
2. Michels-Rautenstrauss et al. (1998) Hum Genet 102: 103-106
3. Stone et al. (1997) Science 275: 668-670.
4. Adam et al.(1997) Hum Mol Genet 6: 2091-1097.
5. Sarfarazi et al. (1997) Hum Mol Genet 6: 1667-1677.
6. Allingham et al. (1997) Am J Hum Genet 61: Poster 1544.
7. Alward et al. (1998) New Eng J Med 338:1022-1027
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