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Mutations in the Myocilin Gene in Families With Primary Open-angle Glaucoma and Juvenile Open-angle Glaucoma
Mirella Bruttini, MS;
Ilaria Longo, MS;
Paolo Frezzotti, MD;
Rossella Ciappetta, MD;
Alessandro Randazzo, MD;
Nicola Orzalesi, MD;
Elena Fumagalli, MD;
Aldo Caporossi, MD;
Renato Frezzotti, MD;
Alessandra Renieri, MD, PhD
Arch Ophthalmol. 2003;121:1034-1038.
ABSTRACT
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Objectives To investigate the prevalence of myocilin (MYOC) mutations in Italian families with glaucoma and to determine the relationship of these mutations to primary open-angle glaucoma (POAG), juvenile open-angle glaucoma (JOAG), and pigmentary dispersion glaucoma.
Methods Twenty-six patients with POAG were selected based on a positive family history of glaucoma. All patients and 210 relatives had an accurate clinical characterization.
Main Outcome Measure Each index patient was screened by single-stranded conformational polymorphism analysis for mutations in the MYOC gene.
Results A MYOC gene mutation was found in 2 families. In one family, a previously reported p.K423E mutation was transmitted from the index patient with POAG to the 2 sons with JOAG. In the second family, a p.C25R change, affecting the signal peptide, was transmitted from the index patient with POAG to the son with JOAG, but not to the son with pigmentary dispersion glaucoma.
Conclusions Clinical characterization of 2 families with MYOC gene mutations indicates that POAG and JOAG are the 2 sides of a continuum phenotypical spectrum due to a common molecular defect. On the other hand, our results confirm the different origin of pigmentary dispersion glaucoma.
Clinical Relevance Because MYOC gene mutations may be responsible for a fraction (2 [8%] of 26) of families with POAG/JOAG, a molecular genetic diagnosis should be included in the management of patients with glaucoma.
INTRODUCTION
PRIMARY OPEN-ANGLE glaucoma (POAG) is the most frequent cause of irreversible blindness in white people, with a 2% prevalence in persons older than 40 years.1 A positive family history for the glaucomatous disease must be considered an important risk factor for POAG.2 Some POAG-associated variables (intraocular pressure [IOP], outflow facility, optic nerve head cupping, and a hypertensive response to corticosteroids) are believed to be inherited.3 The term primary glaucoma includes various clinical entities, such as glaucoma with an elevated IOP (POAG) and normal-tension glaucoma, the relationship of which remains to be elucidated. Ocular hypertension (OH) has to be considered as suspected glaucoma. In young people, glaucoma may be the expression of a late variant of congenital glaucoma, characterized by anterior chamber angle malformations, or an early form of POAG. This latter form is named juvenile open-angle glaucoma (JOAG), and it is believed to be different from the more common adult-onset glaucoma, which usually affects people older than 35 years.4 This form is frequently transmitted as an autosomal dominant trait.5
The first locus for autosomal dominant JOAG, named GLC1A, has been mapped by linkage analysis to chromosome 1q21-q31.5 Subsequently, several other loci named, from GLC1B to GLC1E, and associated with either late-onset glaucoma or normal-pressure glaucoma have been identified.6-10 An additional locus (GLC1F), on chromosome 7q35-q36, has been associated with pigmentary dispersion syndrome (PDS).11 The patients with JOAG linked to the GLC1A locus are characterized by an age of onset of younger than 35 years and an increased IOP, which can be resolved by surgery. In 1997, a gene associated with GLC1A was identified and found to code for a 57-kDa protein called trabecular meshwork–induced glucocorticoid response (TIGR) protein,12 originally described by Polansky et al.13 This protein, recently renamed myocilin (MYOC) (information available at: http://www.gene.ucl.ac.uk/hugo/), is present in many human tissues.14 Although the exact mechanism is unknown, this gene has been implicated in the pathophysiological characteristics of glaucoma by causing obstruction of the aqueous outflow through the trabecular meshwork, resulting in an increased IOP.15 Until recently, when the gene of the GLC1E locus was cloned (optineurin), the MYOC gene was the only known gene for familial glaucoma.16
Several mutations that lead to different characteristic forms of JOAG have been described in the GLC1A gene, which can produce open-angle glaucoma with different clinical findings.14 Approximately 2% to 4% of patients with POAG carry a mutation in the MYOC gene. All of these mutations are located in the coding region, predominantly in the third exon, which encodes a 250–amino acid domain homologous to olfactomedin.17-18 Recent articles14, 19 suggest that the clinical spectrum of the disease, due to MYOC gene mutations, can range from juvenile glaucoma to typical late-onset POAG.
METHODS
PATIENTS
Enrolled patients were collected from 7 centers of ophthalmology located throughout Italy and gave their written informed consent. Patients included in the study underwent a complete ophthalmic examination: an anterior segment examination, determination of uncorrected and best-corrected visual acuity, gonioscopy with grading according to the system of Van Herick et al,20 a fundus examination with a cup-disc ratio evaluation, and a tonometric curve and visual field examination (Program 30-2 on HFA Humphrey Field Analyzer; Humphrey System, Inc, Dublin, Calif). The perimetric defect type and stage evaluation was performed using the Brusini Glaucoma Staging System,21-22 which is a graphic method using a special diagram that classifies the visual field defects into 5 stages of severity and assigns them to 1 of 3 types (generalized, mixed, or localized) based on the mean deviation and the corrected-pattern SD.
At the end of the examination, patients were placed into 1 of 3 groups: (1) those with healthy eyes (not affected by glaucoma), (2) those with OH or suspected glaucoma (IOP >21 mm Hg and no visual field defects), and (3) those affected by POAG. Patients were defined as affected by POAG when they showed at least 2 of the following criteria: glaucomatous visual field defects (based on the corrected-pattern SD and the mean deviation perimetric indexes), OH (IOP >21 mm Hg), and optic nerve head glaucomatous changes (cup-disc ratio >0.7 or notches). Patients included in the study belonged to families in which at least 2 members were affected by POAG. After a clinical examination, a 10-mL blood sample was obtained from each patient. DNA samples of 26 patients (index patients, or probands) and 210 relatives were collected.
MUTATION ANALYSIS
Genomic DNA samples were obtained from the peripheral blood leukocytes of the patients according to standard methods.23 The DNA samples of the 26 probands were screened for MYOC gene mutations using single-stranded conformational polymorphism analysis. The 3 exons of the MYOC gene were amplified by dividing the 2 longer exons into 13 overlapping polymerase chain reaction products. The polymerase chain reaction amplicons were obtained using the primer pairs reported by others.14 The amplification was performed using an amplification system (GeneAmp PCR System 2400; Perkin-Elmer, Norwalk, Conn). For exon amplification, 100 ng of genomic DNA was denatured at 95°C for 5 minutes; mixed with x10 buffer, 0.5-µmol/L primers, 200-µmol/L deoxyribonucleoside triphosphate, and 0.2 U of Taq polymerase (Finnzymes, Espoo, Finland), for a final volume of 25 µL; cycled (x35) at 94°C for 1 minute, 63°C or 66°C for 1 minute, and 72°C for 1 minute; and finally incubated at 72°C for 5 minutes. Amplification products were loaded on precast gradient polyacrylamide gels (GeneGel Exel 12.5/24 Kit; Amersham Pharmacia Biotech, Uppsala, Sweden), after denaturing for 5 minutes at 95°C, and electrophoresed at 250 V for 3 hours 50 minutes, under a controlled temperature of 10°C and/or 20°C. Following the electrophoresis, gels were stained with the silver nitrate method.24 Abnormal polymerase chain reaction products identified by single-stranded conformational polymorphism analysis were sequenced using a genetic analyzer (ABI PRISM 310) and a terminator cycle sequencing kit (BigDye) (PE Applied Biosystems, Foster City, Calif).
RESULTS
Twenty-six patients with POAG (index cases, or probands), belonging to families in which there were at least 2 affected individuals, were screened for mutations in the MYOC gene by single-stranded conformational polymorphism and direct sequencing combined methods. In all families, the most likely transmission of the disease was autosomal dominant. A careful clinical analysis of the families revealed that in 10 of them there was at least 1 affected individual who may be classified as having JOAG (young adults  35 years). The MYOC gene mutation analysis revealed 2 different mutations in 2 probands belonging to this last group. Segregation analysis of mutations in both families and a clinical examination revealed interesting features, which will be described in detail.
FAMILY 1
This is a 3-generation family, in which the proband, aged 74 years, is affected by POAG, with an age of onset of 50 years (Figure 1 and Table 1). His deceased mother was reported to have glaucoma. His son and daughter, aged 40 and 35 years, have JOAG, with an age of onset of glaucoma of 30 and 27 years, respectively. In this family, an A>G transition at the first base of codon 423 in exon 3 of the MYOC gene was found. This substitution caused a missense mutation, changing a lysine at position 423 to a glutamic acid (p.K423E). This mutation is certainly pathogenic because it involves the highly conserved lysine at position 423 in the olfactomedin homologous domain. The same mutation was previously described in patients from a French Canadian family.25-26 Segregation analysis in our family demonstrated that the mutation is present in all affected individuals: the proband with POAG and the 2 sons with JOAG (Figure 1).
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Figure 1. Segregation analysis in family 1. A, Pedigree of the family. Circles indicate females; squares, males; black symbols, individuals with primary open-angle glaucoma or juvenile open-angle glaucoma (the proband is indicated by an arrow); white symbol, unaffected individual; and slash mark, deceased individual. B, Single-stranded conformational polymorphism analysis of segment 3E of exon 3. The primers used are as follows: 5'-GAACTCGAACAAACCTGGGA-3' and 5'-CATGCTGCTGTACTTATAGCGG-3'. The 4 living members of the family were analyzed. The arrowhead indicates the shifted band present in the individuals with mutations; C, control.
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Clinical Data for 2 Families
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FAMILY 2
In this 2-generation family, 5 subjects underwent a clinical examination (Figure 2 and Table 1). The proband, aged 62 years, is affected by POAG. The first son, aged 38 years, was observed the first time at the age of 36 years and was diagnosed as having JOAG; his visual field damage at that time showed that it was a late diagnosis. The second son, aged 30 years, developed OH at the age of 20 years. An examination of his anterior segment revealed signs of PDS. The daughter, aged 28 years, has no signs of glaucoma or OH. Mutation analysis performed in the proband revealed a T>C transition at the first base position of codon 25 in exon 1 of the MYOC gene, resulting in a missense mutation, changing the cysteine at position 25 to an arginine (p.C25R). To our knowledge, this mutation has not been previously described. It affects a cysteine within the signal peptide for secretion of the protein, which covers the first 32 amino acids. Extracellular localization of the native protein is correctly predicted by a computer program (PSORT), with 0.50 of certainty (information available at: http://psort.nibb.ac.jp). If the cysteine at position 25 is substituted by an arginine, the certainty score falls to 0.37, suggesting that in vivo the mutation may lead to a reduction of the protein secretion and indicating a pathogenic role of this novel mutation. Segregation analysis in the family showed that the p.C25R mutation is present in the proband, affected by POAG, and in the first son, affected by JOAG. The mutation is not present in the son with OH and signs of PDS. The combined approach of clinical and molecular analysis suggests that this second son has a different disease.
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Figure 2. Segregation analysis in family 2. A, Pedigree of the family. Circles indicate females; squares, males; black symbols, individuals with primary open-angle glaucoma or juvenile open-angle glaucoma (the proband is indicated by an arrow); white symbols, unaffected individuals; and gray symbol, individual with pigmentary dispersion glaucoma. B, Single-stranded conformational polymorphism analysis of segment 1B of exon 1. The primers used are as follows: 5'-ACGTTGCTCCAGCTTTGG-3' and 5'-GATGACTGACATGGCCTGG-3'. All 5 members of the family were analyzed. The arrowhead indicates the shifted band present in the individuals with mutations; C, control.
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COMMENT
Myocilin is significantly homologous to myosin in the N-terminal region coded by the first and second exon of the MYOC gene and to olfactomedin in the C-terminal region coded by its third exon.27 The olfactomedin homologous domain of the MYOC gene seems to be the focus of pathogenic mutations in patients with POAG. The homology with the olfactomedin protein and the presence of a signal peptide for extracellular localization at its N terminus suggest that MYOC is an extracellular protein. Myocilin is expressed in the eye, including the retina and the structures involved in aqueous humor regulation, such as the ciliary body and the trabecular meshwork.28 The elevated IOP in patients with glaucoma is mainly due to increased resistance to the outflow of aqueous humor from the eye through the trabecular meshwork.28
To better understand the role of the MYOC gene in the pathogenesis of glaucoma, Jacobson et al29 examined the expression of normal and mutant MYOC in cultured ocular and nonocular cells. They demonstrated that, while native MYOC is expressed inside the cells and secreted into the medium, mutated MYOC with the p.K423E change was not secreted into the medium.29 This observation strongly supports the pathogenic role of the p.K423E mutation present in family 1. The mutation of family 2, p.C25R, is located at the N terminus of the MYOC gene, inside the signal peptide sequence necessary for a correct secretion. The strongly reduced secretion of the protein expected for this second missense mutation, suggested by a computer program (PSORT), supports a pathogenic role of this second mutation and a similar final effect with respect to the first mutation.
The biological interactions of mutant MYOC protein and its role in the pathophysiological characteristics of glaucoma are still unclear. On the one hand, the mutations previously described seem to suggest that heterozygous individuals produce insufficient amounts of extracellular MYOC protein (haploinsufficiency hypothesis). On the other hand, glucocorticoid-induced glaucoma and an animal model orient toward a gain-of-function hypothesis.28 In fact, for glucocorticoid-induced glaucoma (in the presence of a normal MYOC protein sequence30), an increased amount of the MYOC protein is present and myoc-null mice, homozygous and heterozygous, are fertile, are viable, and have normal IOP, trabecular meshwork histological features, and retinal and optic nerve morphological features.28 Against the haploinsufficiency hypothesis is also the recent identification of a patient with a deletion of chromosome 1, encompassing the TIGR or MYOC gene, but without clinical signs of glaucoma.31 The gain-of-function hypothesis is also suggested by the fact that in the previously described large French Canadian family with the p.K423E mutation, only heterozygous siblings had glaucoma, whereas 4 homozygous siblings with mutations were asymptomatic for the disease.26 Heteromultimerization of mutant and wild-type forms of the MYOC gene is probably a critical step in the pathogenesis of MYOC-induced glaucoma. These complexes could then lead to an accumulation of aberrant MYOC gene products in the cytoplasm and/or the extracellular matrix, thereby impairing normal aqueous humor outflow.28-29
The p.K423E mutation may be a recurrent mutation in the MYOC gene. Alternatively, a founder effect may be hypothesized, as happens for the hot spot p.G368X.18 Against this hypothesis is the Italian origin of family 1 and the absence of relationships in Canada or in France.
Clinical characterization of the 2 families with the MYOC gene mutation indicates that POAG and JOAG are the 2 sides of a continuum phenotypical spectrum due to a common molecular defect. In one of our families, pigmentary dispersion glaucoma (PDS) was also present. In this family, the p.C25R mutation segregated with POAG and JOAG, but not with PDS. One possible explanation of this result is that the p.C25R substitution is not a disease-causing mutation. Supporting this possibility is the recent finding that some patients with pigmentary glaucoma may have MYOC gene mutations.32-33 Alternatively, patients affected by PDS may have a different disease. Supporting this hypothesis is the in silico prediction (ie, computer-based prediction) of reduced secretion of the mutant protein and linkage analysis studies34-36 demonstrating locus heterogeneity for PDS. In fact, POAG and PDS have long been considered 2 clinically different diseases,37-38 and it is conceivable that patients affected by PDS in family 2 may have a mutation in another yet uncovered gene.
The results of our study confirm that MYOC gene mutations may be responsible for a fraction (2 [8%] of 26) of families with POAG/JOAG with autosomal dominant inheritance. Because of the low detection rate, a MYOC investigation can be effective only in a subset of patients with familial glaucoma. However, within the few families in whom a causative mutation is found, a molecular genetic test may have great relevance in terms of presymptomatic diagnosis for relatives, who may benefit from early treatment. In conclusion, molecular genetic diagnosis could become interesting in the study and management of patients with familial glaucoma.
AUTHOR INFORMATION
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Corresponding author and reprints: Alessandra Renieri, MD, PhD, Division of Medical Genetics, University of Siena, Policlinico Le Scotte viale Bracci 2, 53100 Siena, Italy (e-mail: renieri{at}unisi.it).
Submitted for publication August 22, 2002; final revision received February 18, 2003; accepted March 6, 2003.
This study was supported by grant MURST 99 from the Italian Ministry of Education, University, and Research, Rome (Drs R. Frezzotti and Renieri).
We thank Stefano Gandolfi, MD, Federico Grignolo, MD, and Laura Tomazzoli, MD, for supplying samples and performing the clinical analysis; and Maddalena Muscettola, BS, and Barbara Palumbo for performing the single-stranded conformational polymorphism analysis.
Mss Bruttini and Longo contributed equally to this study.
From the Division of Medical Genetics, Department of Molecular Biology (Mss Bruttini and Longo and Dr Renieri), the Department of Ophthalmology (Drs P. Frezzotti, Ciappetta, and Caporossi), and Emeritus Professor R. Frezzotti, University of Siena, Siena, Italy; and the Department of Ophthalmology, University of Milan, Milan, Italy (Drs Randazzo, Orzalesi, and Fumagalli). The authors have no relevant financial interest in this article.
REFERENCES
1. Leske MC. The epidemiology of open-angle glaucoma: a review. Am J Epidemiol. 1983;118:166-191.
FREE FULL TEXT
2. Wolfs RC, Klaver CC, Ramrattan RS, et al. Genetic risk of primary open-angle glaucoma: population-based familial aggregation study. Arch Ophthalmol. 1998;116:1640-1645.
FREE FULL TEXT
3. Armaly MF. Corticosteroid glaucoma. In: Cairns JE, ed. Glaucoma. Vol II. London, England: Grune & Stratton; 1986:697-710.
4. European Glaucoma Society. Terminology and Guidelines for Glaucoma. Savona, Italy: editrice Dogma; 1998.
5. Sheffield VC, Stone EM, Alward WLM, et al. Genetic linkage of familial open angle glaucoma to chromosome 1q21-q31. Nat Genet. 1993;4:47-50.
FULL TEXT
|
ISI
| PUBMED
6. 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;36:142-150.
FULL TEXT
|
ISI
| PUBMED
7. Wirtz MK, Samples JR, Kramer P, et al. Mapping a gene for adult-onset primary open-angle glaucoma to chromosome 3q. Am J Hum Genet. 1997;60:296-304.
ISI
| PUBMED
8. 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.
FULL TEXT
|
ISI
| PUBMED
9. Sarfarazi M. Recent advances in molecular genetics of glaucomas. Hum Mol Genet. 1997;6:1667-1677.
FREE FULL TEXT
10. 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;62:641-652.
FULL TEXT
|
ISI
| PUBMED
11. Wirtz MK, Samples JR, Rust K, et al. GLC1F, a new primary open-angle glaucoma locus, maps to 7q35-q36. Arch Ophthalmol. 1999;117:237-241.
FREE FULL TEXT
12. Stone EM, Fingert JH, Alward WLM, et al. Identification of a gene that causes primary open angle glaucoma. Science. 1997;275:668-670.
FREE FULL TEXT
13. Polansky JR, Kurtz R, Alvarado J, Weinreb R, Mitchell M. Eicosanoid production and glucocorticoid regulatory mechanisms in cultured human trabecular meshwork cells. Prog Clin Biol Res. 1989;312:113-138.
PUBMED
14. Alward WLM, Fingert JH, Coote MA, et al. Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A). N Engl J Med. 1998;338:1022-1027.
FREE FULL TEXT
15. Mabuchi F, Yamagata Z, Kashiwagi K, et al. Analysis of myocilin gene mutations in Japanese patients with normal tension glaucoma and primary open-angle glaucoma. Clin Genet. 2001;59:263-268.
FULL TEXT
|
ISI
| PUBMED
16. Rezaie T, Child A, Hitchings R, et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002;295:1077-1079.
FREE FULL TEXT
17. Adam MF, Belmouden A, Binisti P, 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.
FREE FULL TEXT
18. Fingert JH, Heon E, Liebmann JM, et al. Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet. 1999;8:899-905.
FREE FULL TEXT
19. Angius A, Spinelli P, Ghilotti G, et al. Myocilin Gln368stop mutation and advanced age as risk factors for late-onset primary open-angle glaucoma. Arch Ophthalmol. 2000;118:674-679.
FREE FULL TEXT
20. Van Herick W, Shaffer RN, Schwartz A. Estimation of width of angle of anterior chamber: incidence and significance of the narrow angle. Am J Ophthalmol. 1969;68:626-629.
ISI
| PUBMED
21. Brusini P. Clinical use of a new method for visual field damage classification in glaucoma. Eur J Ophthalmol. 1996;6:402-407.
PUBMED
22. Kocak I, Zalauf M, Bergamin O. Evaluation of the Brusini Glaucoma Staging System for typing and staging of perimetric results. Ophthalmologica. 1998;212:221-227.
FULL TEXT
|
ISI
| PUBMED
23. Sambrook J, Fritsch E, Maniatis T. Molecular Cloning: A Laboratory Manual. New York, NY: CSHL Press; 1989.
24. Renieri A, Bruttini M, Galli L. X-linked Alport syndrome: an SSCP-based mutation survey over all 51 exons of the COL4A5 gene. Am J Hum Genet. 1996;58:1192-1204.
ISI
| PUBMED
25. Morissette J, Cote G, Anctil J, 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.
ISI
| PUBMED
26. Morissette J, Clepet C, Moisan S, et al. Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma. Nat Genet. 1998;19:319-321.
FULL TEXT
|
ISI
| PUBMED
27. Kubota R, Noda S, Wang Y, et al. A novel myosin-like protein (myocilin) expressed in the connecting cilium of the photoreceptor: molecular cloning, tissue expression, and chromosomal mapping. Genomics. 1997;41:360-369.
FULL TEXT
|
ISI
| PUBMED
28. Kim BS, Savinova OV, Reedy MV, et al. Targeted disruption of the myocilin gene (MYOC) suggests that human glaucoma-causing mutations are gain of function. Mol Cell Biol. 2001;21:7707-7713.
FREE FULL TEXT
29. Jacobson N, Andrews M, Shepard AR, 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.
FREE FULL TEXT
30. Fingert JH, Clark AF, Craig JE, et al. Evaluation of the myocilin (MYOC) glaucoma gene in monkey and human steroid-induced ocular hypertension. Invest Ophthalmol Vis Sci. 2001;42:145-152.
FREE FULL TEXT
31. Wiggs JL, Vollrath D. Molecular and clinical evaluation of a patient hemizygous for TIGR/MYOC. Arch Ophthalmol. 2001;119:1674-1678.
FREE FULL TEXT
32. Alward WLM, Kwon YH, Khanna CL, et al. Variations in the myocilin gene in patients with open-angle glaucoma. Arch Ophthalmol. 2002;120:1189-1197.
FREE FULL TEXT
33. Faucher M, Anctil JL, Rodrigue MA, et al. Founder TIGR/myocilin mutations for glaucoma in the Québec population. Hum Mol Genet. 2002;11:2077-2090.
FREE FULL TEXT
34. Andersen JS, Pralea AM, DelBono EA, et al. A gene responsible for the pigment dispersion syndrome maps to chromosome 7q35-q36. Arch Ophthalmol. 1997;115:384-388.
ABSTRACT
35. Andersen JS, Parrish R, Greenfield D, et al. A second locus for pigment dispersion syndrome and pigmentary glaucoma maps to 18q11-q21 [abstract]. Am J Hum Genet. 1998;63(suppl):A279.
36. Ritch R. Going forward to work backward [editorial]. Arch Ophthalmol. 1997;115:404-405.
ISI
| PUBMED
37. Spencer WH, Font RL, Green WR, et al. Glaucoma. In: Ophthalmic Pathology: An Atlas and Textbook. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1984:84-98.
38. Zink HA, Palmberg PF, Sugar A, et al. Comparison of in vitro corticosteroid response in pigmentary glaucoma and primary open-angle glaucoma. Am J Ophthalmol. 1975;80:478-484.
ISI
| PUBMED
SECTION EDITOR: EDWIN M. STONE, MD, PhD
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