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Abstract #8904 Published in IGR 5-2
Glaucoma phenotype in pedigrees with the myocilin Thr377Met mutation
Mackey DA; Healey DL; Fingert JH; Coote MA; Wong TL; Wilkinson CH; McCartney PJ; Rait JL; De Graaf AP; Stone EMArchives of Ophthalmology 2003; 121: 1172-1180
OBJECTIVE: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the myocilin mutation Thr377Met. METHOD AND DESIGN: Cross-sectional genetic study. Four unrelated pedigrees carrying the Thr377Met mutation were ascertained from more than 2000 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania and from families with glaucoma referred to the study from throughout Australia. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Thr377Met mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. RESULTS: From the four pedigrees carrying the Thr377Met mutation, 23 individuals with either ocular hypertension (OHT) or POAG were found, with a mean ± SD age at diagnosis of 41.2 ± 11.5 years, and a mean peak intraocular pressure (IOP) of 31.7 ± 9.9 mmHg. A further nine mutation carriers older than 18 years were studied who as yet showed no signs of OHT or POAG (six of these nine were younger than 30 years). A single individual with POAG was identified who did not carry the Thr377Met mutation. For Thr377Met carriers, age-related penetrance for OHT or POAG was 88% at the age of 30 years. A positive family history of POAG was present in three of the four index cases. Thirteen (57%) of the 23 Thr377Met carriers with OHT or POAG had undergone glaucoma drainage surgery. Although the glaucoma in these families appears to be pressure dependent, two individuals showed optic disc cupping before detected elevation in IOP. One family was of British origin, with a different background haplotype from the other three families from Greece or Macedonia, who shared a common haplotype. CONCLUSIONS: The GLC1A Thr377Met mutation is associated with POAG that, in the pedigrees studied, had a younger age at onset and higher peak IOP than in pedigrees with the more common Gln368STOP mutation. In addition, patients with glaucoma with the Thr377Met mutation were more likely to have undergone glaucoma drainage surgery.
Dr. D.A. Mackey, Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia
Classification:
1.2 Population genetics (Part of: 1 General aspects)