Glaucoma Genetics Scorecard – 2003 

Wallace L.M. Alward, M.D.

University of Iowa College of Medicine

Updated December 10, 2003

Chromosomal locations are typically discovered by linkage analysis within a large family or a group of families. A linkage localizes a disease-causing gene to a chromosomal region that may contain thousands of genes. The strength of a linkage is determined by the logarithm of the odds (lod score). A lod score over 3 is considered significant for linkage. Some of the reported linkages (such as GLC1A) have been confirmed by many laboratories and have very high lod scores. Some other linkages have barely significant lod scores and have never been confirmed. Some may ultimately prove to be false.

When there is a gene listed it means that a mutation in this gene has been reported in a patient with the particular glaucoma. It may be a strong association or it may be that a large series of patients with a variety of glaucomas was screened and a single patient was found to have a mutation. For example, a large number of patients with a variety of open-angle glaucomas was screened for myocilin mutations. Of 60 patients with exfoliative glaucoma, 1 (1.7%) had a myocilin mutation. ¹ Myocilin mutations can be found in patients with exfoliation syndrome but it is not a major cause of this disease.

I have attempted to make this as accurate and current as possible. I apologize for any errors or omissions.

Glaucoma Genetics Scorecard

The inheritance of diseases commonly associated with glaucoma

By Disease

* The approximate prevalence of these mutations is given for those genes that have been studied in large prevalence studies.

** Alward WLM, Kwon YH, Kawase K, et.al. Evaluation of optineurin sequence variations in 1,048 patients with open angle glaucoma. Am J Ophthalmolol, in press 2003.

S.C. = single case report
By Gene

MIM = Mendelian Inheritance in Man

Online Mendelian Inheritance in Man (OMIM) is on the web at:

            http://www.ncbi.nlm.nih.gov/omim/

These tables list diseases that have glaucoma as a major feature and for which at least one genetic locus has been identified. There are many rare syndromes that have glaucoma as a minor component and these are not included in this list. The latter are reviewed in Johnson et al. ⁵⁰

References

1.         Alward WL, Kwon YH, Khanna CL, et al. Variations in the myocilin gene in patients with open-angle glaucoma. Arch Ophthalmol 2002;120:1189-97.

2.         Sheffield VC, Stone EM, Alward WLM, et al. Genetic linkage of familial open angle glaucoma to chromosome 1q21-q31. Nature Genetics 1993;4:47-50.

3.         Stone EM, Fingert JH, Alward WLM, et al. Identification of a gene that causes primary open angle glaucoma. Science 1997;275:668-670.

4.         Stoilova D, Child A, Trifan OC, Crick RP, Coakes RL, Sarfarazi M. Localization of a locus (GLC1B) for adult-onset primary open angle glaucoma to the 2cen-q13 region. Genomics 1996;36:142-50.

5.         Wirtz MK, Samples JR, Kramer PL, et al. Mapping a gene for adult-onset primary open-angle glaucoma to chromosome 3q [see comments]. Am J Hum Genet 1997;60:296-304.

6.         Trifan OC, Traboulsi EI, Stoilova D, et al. A third locus (GLC1D) for adult-onset primary open-angle glaucoma maps to the 8q23 region. Am J Ophthalmol 1998;126:17-28.

7.         Wirtz MK, Samples JR, Rust K, et al. GLC1F, a new primary open-angle glaucoma locus, maps to 7q35-q36 [In Process Citation]. Arch Ophthalmol 1999;117:237-41.

8.         Alward WL, Fingert JH, Coote MA, et al. Clinical features associated with mutations in the chromosome 1 open- angle glaucoma gene (GLC1A) [see comments]. N Engl J Med 1998;338:1022-7.

9.         Sarfarazi M, Child A, Stoilova D, et al. Localization of the Fourth Locus (GLC1E) For Adult-Onset Primary Open- Angle Glaucoma to the 10p15-p14 Region. Am J Hum Genet 1998;62:641-52.

10.        Rezaie T, Child A, Hitchings R, et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 2002;295:1077-9.

11.        Mardin CY, Velten I, Ozbey S, Rautenstrauss B, Michels-Rautenstrauss K. A GLC1A gene Gln368Stop mutation in a patient with normal-tension open- angle glaucoma [In Process Citation]. J Glaucoma 1999;8:154-6.

12.        Aung T, Ocaka L, Ebenezer ND, et al. A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene. Hum Genet 2002;110:52-6.

13.        Vickers JC, Craig JE, Stankovich J, et al. The apolipoprotein epsilon4 gene is associated with elevated risk of normal tension glaucoma. Mol Vis 2002;8:389-93.

14.        Lichter PR, Richards JE, Downs CA, Stringham HM, Boehnke M, Farley FA. Cosegregation of open-angle glaucoma and the nail-patella syndrome. American Journal of Ophthalmology 1997;124:506-515.

15.        Andersen JS, Pralea AM, DelBono EA, et al. A gene responsible for the pigment dispersion syndrome maps to chromosome 7q35-q36 [see comments]. Arch Ophthalmol 1997;115:384-8.

16.        Andersen JS, Parrish R, Greenfield D, DelBono EA, Haines JL, Wiggs JL. A second locus for the pigment dispersion syndrome and pigmentary glaucoma maps to 18q11-q21. Am J Hum Genet 1998;63:A279.

17.        Othman MI, Sullivan SA, Skuta GL, et al. Autosomal dominant nanophthalmos (NNO1) with high hyperopia and angle- closure glaucoma maps to chromosome 11. Am J Hum Genet 1998;63:1411-8.

18.        Morle L, Bozon M, Zech JC, et al. A locus for autosomal dominant colobomatous microphthalmia maps to chromosome 15q12-q15. Am J Hum Genet 2000;67:1592-7.

19.        Sarfarazi M, Akarsu AN, Hossain A, et al. Assignment of a locus (GLC3A) for primary congenital glaucoma (buphthalmos) to 2p21 and evidence of genetic heterogeneity. Genomics 1995;30:171-177.

20.        Stoilov I, Akarsu AN, Sarfarazi M. Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Hum Mol Genet 1997;6:641-7.

21.        Akarsu AN, Turacli ME, Aktan SG, et al. A second locus (GLC3B) for primary congenital glaucoma (Buphthalmos) maps to the 1p36 region. Hum Mol Genet 1996;5:1199-203.

22.        Nishimura DY, Swiderski RE, Alward WL, et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat Genet 1998;19:140-7.

23.        Simola KO, Knuutila S, Kaitila I, Pirkola A, Pohja P. Familial aniridia and translocation t(4;11)(q22;p13) without Wilms' tumor. Hum Genet 1983;63:158-61.

24.        Ton CCT, Hirvonen H, Miwa H, et al. Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region. Cell 1991;67:1059-1074.

25.        Larsson C, Hellqvist M, Pierrou S, White I, Enerback S, Carlsson P. Chromosomal localization of six human forkhead genes, freac-1 (FKHL5), - 3 (FKHL7), -4 (FKHL8), -5 (FKHL9), -6 (FKHL10), and -8 (FKHL12). Genomics 1995;30:464-9.

26.        Semina EV, Brownell I, Mintz-Hittner HA, Murray JC, Jamrich M. Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum Mol Genet 2001;10:231-6.

27.        Semina EV, Ferrell RE, Mintz-Hittner HA, et al. A novel homeobox gene PITX3 is mutated in families with autosomal- dominant cataracts and ASMD. Nat Genet 1998;19:167-70.

28.        Shields MB, Buckley E, Klintworth GK, Thresher R. Axenfeld-Rieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol 1985;29:387-409.

29.        Alward WL. Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Ophthalmol 2000;130:107-15.

30.        Gould DB, Mears AJ, Pearce WG, Walter MA. Autosomal dominant Axenfeld-Rieger anomaly maps to 6p25 [letter]. Am J Hum Genet 1997;61:765-8.

31.        Mears AJ, Mirzayans F, Gould DB, Pearce WG, Walter MA. Autosomal dominant iridogoniodysgenesis anomaly maps to 6p25. Am J Hum Genet 1996;59:1321-7.

32.        Héon E, Sheth B, Kalenak J, et al. Linkage of autosomal dominant iris hypoplasia to the region of the Rieger syndrome locus (4q25). Human Molecular Genetics 1995;4:1435-1439.

33.        Alward WLM, Semina EV, Kalenak JW, et al. Autosomal dominant iris hypoplasia is caused by a mutation in the Rieger syndrome (RIEG/PITX2) gene. American Journal of Ophthalmology 1998;125:98-100.

34.        Murray JC, Bennett SR, Kwitek AE, et al. Linkage of Rieger syndrome to the region of the epidermal growth factor gene on chromosome 4. Nature Genetics 1992;2:46-49.

35.        Semina EV, Reiter R, Leysens NJ, et al. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RGS, involved in Rieger syndrome. Nature Genetics 1996;14:392-399.

36.        Phillips JC, del Bono EA, Haines JL, et al. A second locus for Rieger syndrome maps to chromosome 13q14. Am J Hum Genet 1996;59:613-9.

37.        Edwards MJ, Challinor CJ, Colley PW, et al. Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1. Am J Med Genet 1994;53:65-71.

38.        Streiff EB, Straub W, Golay L. Les manifestations oculaires du syndrome de Lowe. Ophthalmologica 1958;135:632-639.

39.        Attree O, Olivos IM, Okabe I, et al. The Lowe's oculocerebrorenal syndrome gene encodes a protein highy homologous to inositol polyphosphate-5-phosphatase. Nature 1992;358:239-242.

40.        Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L. Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 1990;323:935-9.

41.        Haefliger IO, Flammer J. Fluctuation of the differential light threshold at the border of absolute scotomas - comparison between glaucomatous visual field defects and blind spots. Ophthalmology 1991;98:1529-1532.

42.        Barker D, Wright E, Nguyen K, et al. Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science 1987;236:1100-2.

43.        Gutmann DH, Collins FS. The neurofibromatosis type 1 gene and its protein product, neurofibromin. Neuron 1993;10:335-43.

44.        Hanson IM, Fletcher JM, Jordan T, et al. Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly. Nat Genet 1994;6:168-73.

45.        Vincent A, Gail Billingsley, Megan Priston, Donna Williams-Lyn, Joanne Sutherland, Tom Glaser, Edward Oliver, Michael A. Walter, Godfrey Heathcote, Alex Levin, Elise Héon. Phenotypic heterogeneity of GYP1B1: mutations in a patient with Peters' anomaly. J med Genet 2001;2001:324-326.

46.        Doward W, Perveen R, Lloyd IC, Ridgway AE, Wilson L, Black GC. A mutation in the RIEG1 gene associated with Peters' anomaly. J Med Genet 1999;36:152-5.

47.        Honkanen RA, Nishimura DY, Swiderski RE, et al. A family with Axenfeld-Rieger syndrome and Peters Anomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene. Am J Ophthalmol 2003;135:368-75.

48.        Héon E, Mathers W, Alward W, et al. Linkage of posterior polymorphous corneal dystrophy to 20q11. Human Molecular Genetics 1995;4:485-488.

49.        Héon E, Greenberg A, Kopp KK, et al. VSX1: a gene for posterior polymorphous dystrophy and keratoconus. Hum Mol Genet 2002;11:1029-36.

50.        Johnson AT, Alward WLM, Sheffield VC, Stone EM. Genetics and Glaucoma, 2nd ed. In: Ritch R, Shields MB, Krupin T, editors. The Glaucomas. St. Louis: C.V. Mosby, 1996:39-54.