Abstract
Aims
To characterize genotype, phenotype, and age-related penetrance in a Swiss pedigree with juvenile open-angle glaucoma (JOAG).
Methods
In a large Swiss family with history of glaucoma and 82 living members of four generations, we conducted molecular analysis and a detailed phenotype characterization in 52 family members. Mutation analysis was carried out using single-strand conformation polymorphism and DNA sequence analyses of the suspected candidate gene, myocilin (MYOC).
Results
We detected a Gly367Arg mutation in the MYOC gene of 13 family members. Nine of them (69.2%) had glaucoma: mean IOP 35.3 mm Hg, range 24–50 mm Hg; mean age at diagnosis 34.9 years, range 28–51 years. Two mutation carriers were glaucoma suspects, one (age 15) was unaffected, and one (age 16) not available for clinical examinations. Age-related glaucoma penetrance was 50% at 30 and 78% at 40. Untreated IOP resulted in rapid disease progression, whereas good IOP control, usually only by means of filtration surgery, could stabilize the disease. None of the wild-type members had glaucoma.
Conclusions
This Swiss family is the largest reported Gly367Arg pedigree to date. The exact genotype and phenotype characterization allowed a reliable risk and prognosis assessment and targeted eye-care planning for the family. The study demonstrates the importance of genetic investigations in glaucoma families, carrying the potential of long-term socio-economic benefits.
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References
Leske MC . The epidemiology of open-angle glaucoma: a review. Am J Epidemiol 1983; 118: 166–191.
Quigley HA . Number of people with glaucoma worldwide. Br J Ophthalmol 1996; 80: 389–393.
Resnikoff S, Pascolini D, Etya'ale D, Kocur I, Pararajasegaram R, Pokharel GP et al. Global data on visual impairment in the year 2002. Bull World Health Organ 2004; 82: 844–851.
Hewitt AW, Craig JE, Mackey DA . Complex genetics of complex traits: the case of primary open-angle glaucoma. Clin Experiment Ophthalmol 2006; 34: 472–484.
Monemi S, Spaeth G, DaSilva A, Popinchalk S, Ilitchev E, Liebmann J et al. Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1. Hum Mol Genet 2005; 14: 725–733.
Alward WL, Fingert JH, Coote MA, Johnson AT, Lerner SF, Junqua D et al. Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A). N Engl J Med 1998; 338: 1022–1027.
Fingert JH, Heon E, Liebmann JM, Yamamoto T, Craig JE, Rait J et al. Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet 1999; 8: 899–905.
Sheffield VC, Stone EM, Alward WL, Drack AV, Johnson AT, Streb LM et al. Genetic linkage of familial open angle glaucoma to chromosome 1q21–q31. Nat Genet 1993; 4: 47–50.
Stone EM, Fingert JH, Alward WL, Nguyen TD, Polansky JR, Sunden SL et al. Identification of a gene that causes primary open angle glaucoma. Science 1997; 275: 668–670.
Baird PN, Richardson AJ, Mackey DA, Craig JE, Faucher M, Raymond V . A common disease haplotype for the Q368STOP mutation of the myocilin gene in Australian and Canadian glaucoma families. Am J Ophthalmol 2005; 140: 760–762.
Mabuchi F, Yamagata Z, Kashiwagi K, Tang S, Iijima H, Tsukahara S . Analysis of myocilin gene mutations in Japanese patients with normal tension glaucoma and primary open-angle glaucoma. Clin Genet 2001; 59: 263–268.
Morissette J, Cote G, Anctil JL, Plante M, Amyot M, Heon E et al. A common gene for juvenile and adult-onset primary open-angle glaucomas confined on chromosome 1q. Am J Hum Genet 1995; 56: 1431–1442.
Morissette J, Clepet C, Moisan S, Dubois S, Winstall E, Vermeeren D et al. Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma. Nat Genet 1998; 19: 319–321.
Liechti-Gallati S, Schneider V, Neeser D, Kraemer R . Two buffer PAGE system-based SSCP/HD analysis: a general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease. Eur J Hum Genet 1999; 7: 590–598.
Jacobson N, Andrews M, Shepard AR, Nishimura D, Searby C, Fingert JH et al. Non-secretion of mutant proteins of the glaucoma gene myocilin in cultured trabecular meshwork cells and in aqueous humor. Hum Mol Genet 2001; 10: 117–125.
Suzuki Y, Shirato S, Taniguchi F, Ohara K, Nishimaki K, Ohta S . Mutations in the TIGR gene in familial primary open-angle glaucoma in Japan. Am J Hum Genet 1997; 61: 1202–1204.
Taniguchi F, Suzuki Y, Shirato S, Araie M . The Gly367Arg mutation in the myocilin gene causes adult-onset primary open-angle glaucoma. Jpn J Ophthalmol 2000; 44: 445–448.
Michels-Rautenstrauss KG, Mardin CY, Budde WM, Liehr T, Polansky J, Nguyen T et al. Juvenile open angle glaucoma: fine mapping of the TIGR gene to 1q24.3–q25.2 and mutation analysis. Hum Genet 1998; 102: 103–106.
Mansergh FC, Kenna PF, Ayuso C, Kiang AS, Humphries P, Farrar GJ . Novel mutations in the TIGR gene in early and late onset open angle glaucoma. Hum Mutat 1998; 11: 244–251.
Faucher M, Anctil JL, Rodrigue MA, Duchesne A, Bergeron D, Blondeau P et al. Founder TIGR/myocilin mutations for glaucoma in the Quebec population. Hum Mol Genet 2002; 11: 2077–2090.
Kanagavalli J, Krishnadas SR, Pandaranayaka E, Krishnaswamy S, Sundaresan P . Evaluation and understanding of myocilin mutations in Indian primary open angle glaucoma patients. Mol Vis 2003; 9: 606–614.
Angius A, De Gioia E, Loi A, Fossarello M, Sole G, Orzalesi N et al. A novel mutation in the GLC1A gene causes juvenile open-angle glaucoma in 4 families from the Italian region of Puglia. Arch Ophthalmol 1998; 116: 793–797.
Adam MF, Belmouden A, Binisti P, Brezin AP, Valtot F, Bechetoille A et al. Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma. Hum Mol Genet 1997; 6: 2091–2097.
Brezin AP, Adam MF, Belmouden A, Lureau MA, Chaventre A, Copin B et al. Founder effect in GLC1A-linked familial open-angle glaucoma in Northern France. Am J Med Genet 1998; 76: 438–445.
Lam DS, Leung YF, Chua JK, Baum L, Fan DS, Choy KW et al. Truncations in the TIGR gene in individuals with and without primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2000; 41: 1386–1391.
Mackey DA, Healey DL, Fingert JH, Coote MA, Wong TL, Wilkinson CH et al. Glaucoma phenotype in pedigrees with the myocilin Thr377Met mutation. Arch Ophthalmol 2003; 121: 1172–1180.
Craig JE, Baird PN, Healey DL, McNaught AI, McCartney PJ, Rait JL et al. Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier. Ophthalmology 2001; 108: 1607–1620.
Swiderski RE, Ross JL, Fingert JH, Clark AF, Alward WL, Stone EM et al. Localization of MYOC transcripts in human eye and optic nerve by in situ hybridization. Invest Ophthalmol Vis Sci 2000; 41: 3420–3428.
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We thank all the participants in this study for their commitment.
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Iliev, M., Bodmer, S., Gallati, S. et al. Glaucoma phenotype in a large Swiss pedigree with the myocilin Gly367Arg mutation. Eye 22, 880–888 (2008). https://doi.org/10.1038/sj.eye.6702745
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DOI: https://doi.org/10.1038/sj.eye.6702745
