IOVS Molecular Human Reproduction
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lam, D. S. C.
Right arrow Articles by Pang, C. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lam, D. S. C.
Right arrow Articles by Pang, C. P.
(Investigative Ophthalmology and Visual Science. 2000;41:1386-1391.)
© 2000 by The Association for Research in Vision and Ophthalmology, Inc.

Truncations in the TIGR Gene in Individuals with and without Primary Open-Angle Glaucoma

Dennis S. C. Lam, Yuk Fai Leung, John K. H. Chua, Larry Baum, Dorothy S. P. Fan, Kwong Wai Choy and Chi Pui Pang

From the Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To investigate the coding exons in the trabecular meshwork–induced glucocorticoid response protein (TIGR) gene for mutations in primary open-angle glaucoma (POAG) in Chinese subjects.

METHODS. Ninety-one Chinese patients with POAG and 113 of their family members without glaucoma were screened for sequence alterations in the TIGR gene by polymerase chain reaction, conformation-sensitive gel electrophoresis, and DNA sequencing. One hundred thirty-two unrelated individuals without glaucoma, aged 50 years or more, were studied as control subjects.

RESULTS. Five sequence variants that lead to amino acid changes were identified. One was novel: Arg91Stop in one patient with POAG. Four had been reported: Arg46Stop in subjects with and without POAG, including an unaffected 77-year-old woman homozygous for Arg46Stop; Gly12Arg in subjects without glaucoma; and Asp208Glu and Thr353Ile in subjects with and without POAG. The previously reported 1-83(G->A) and Arg76Lys polymorphisms were detected in both patients and controls and always occurred together.

CONCLUSIONS. A different pattern of TIGR sequence variants exists in the Chinese than in non-Chinese populations. No common TIGR mutation that causes POAG was found. The occurrence of subjects without glaucoma who are heterozygous or homozygous for Arg46Stop suggests that reduction in the amount of TIGR protein does not cause glaucoma. Thus, the TIGR missense mutations known to cause POAG probably do not cause glaucoma by inactivating a normal TIGR function, but rather through the gain of a pathologic function.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Glaucoma is a complex and progressive disorder of the optic nerves and a leading cause of visual field defects and blindness in developed countries.1 Primary open-angle glaucoma (POAG), which affects almost 2% of the world’s population, accounts for most glaucoma.2 Onset of the disease can occur at young age or later in life, but the prevalence increases with age. The pathophysiology of POAG is not precisely known although its cause is clearly multifactorial. It is a result of multiple and interactive genetic and environmental effects. Risk factors include positive family history, age, hypertension, diabetes, smoking, and alcohol consumption.3 4 5

At least six associated chromosomal loci have been located for POAG: GLC1A, GLC1B, GLC1C, GLC1D, GLC1E, and GLC1F on chromosomes 1q24-25, 2cen-q13, 3q21-24, 8q23, 10p, and 7q35-36 respectively.6 7 GLC1A codes for the myocilin polypeptide, also known as the trabecular meshwork–inducible glucocorticoid response protein (TIGR).8 TIGR is expressed in many eye tissues including sclera, ciliary body, trabecular meshwork (TM), and retina, as well as in nonocular tissues such as heart, lung, and pancreas.9 10 11 In the TM cells, although the mechanism is unknown, it is suggested that mutated TIGR proteins expressed from TIGR variants may disturb the normal cytoskeletal function or block the movement of aqueous humor through the extracellular spaces. Glucocorticoid causes overexpression and secretion of TIGR by cultured TM cells, and topical glucocorticoid treatment induces intraocular pressure (IOP) elevation in some patients with POAG.12 Thus, production of mutated TIGR protein with altered structures or inappropriately high levels of TIGR protein may contribute to glaucoma pathogenesis, causing IOP elevation. In fact, certain TIGR mutations have been shown to be associated with clinical IOP elevations in patients with glaucoma who are carriers of the mutations.13

The TIGR gene spans 20 kb and includes three exons. Its promoter region is characterized by multiple-consensus steroid hormone–responsive elements, besides other important regulatory motifs.10 There have been more than 30 sequence variants reported for the TIGR gene within its structural domains. Among them, at least 16 (Table 1) were shown to have strong associations with POAG.8 10 13 14 15 16 17 18 19 20 21 22 23 24 25 The sequence changes were mainly found to be associated with exon 3 and included missense and nonsense mutations. Some sequence variants in exon 1 have been called probable glaucoma-causing mutations,13 18 26 but the number of subjects studied was not large enough to confirm an association with POAG. However, most sporadic occurrences of POAG do not occur in patients with mutations in TIGR.13 18 21 The prevalence of POAG is affected by ethnicity. American blacks have a significantly higher frequency than American whites.2 Ethnic difference in the frequency of TIGR mutations among patients with POAG has not been well examined, but one large study reported a range from 2.6% to 4.3% among Japanese, African-Americans, and whites.18 So far there has been no report on TIGR mutations in Chinese. In this study, we screened for TIGR sequence alterations in Chinese subjects with and without POAG.


View this table:
[in this window]
[in a new window]
  		Table 1. Published Glaucoma-Associated TIGR Mutations

 

   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Patients with POAG were recruited from the Eye Clinic of the Prince of Wales Hospital, Hong Kong. Diagnosis of POAG required all the following: exclusion of secondary causes (e.g., trauma, uveitis, or steroid-induced or neovascular glaucoma); open anterior chamber angle; IOP higher than 21 mm Hg; characteristic optic disc changes (e.g., vertical cup-to-disc ratio higher than 0.3); thin or notched neuroretinal rim or disc hemorrhage; and characteristic visual field changes with reference to Anderson’s criteria for minimal abnormality in glaucoma.27

Persons with POAG ranged in age from 8 to 77 years, with a mean and median of 44.5 and 40.5 years, respectively. Some patients’ relatives who did not have glaucoma were also included in the study. Unrelated control subjects were recruited from patients who attended the clinic for conditions other than glaucoma, including cataract, floaters, refractive errors, and itchy eyes. All control subjects were at least 50 years of age. All study subjects were given a complete ocular examination, and venous blood was collected and stored at -20°C for less than 2 months before DNA extraction. The study protocol was approved by the Ethics Committee for Human Research, the Chinese University of Hong Kong, and followed the tenets of the Declaration of Helsinki. Informed consent was obtained from the study subjects after explanation of the nature and possible consequences of the study.

Polymerase Chain Reaction
Genomic DNA was extracted from 200 µl of whole blood using a kit (Qiamp; Qiagen, Hilden, Germany). The coding sequence of TIGR was screened for sequence alterations using polymerase chain reaction (PCR) followed by conformation-sensitive gel electrophoresis (CSGE). CSGE is an optimized heteroduplex method that can detect heterozygous mutations that are not closer than approximately 40 bases from the end of a DNA fragment, in DNA fragments less than approximately 500 bases.31 32 Thus, the three exons of TIGR were amplified by dividing the two longer exons into overlapping PCR products of less than 500 bases each. The seven PCR amplicons were obtained using the primer pairs in Table 2 . For the PCR thermal cycle, a touchdown annealing temperature of 62°C minus 0.2°C per cycle for 35 cycles was used in a thermal cycler (model 9700; Perkin–Elmer, Foster City, CA). Each 25-µl reaction contained 1.5 mM MgCl2, 1 U Taq polymerase, 200 µM dNTPs, and 2.5 µl PCR buffer (Gibco, Gaithersburg, MD), as well as 1 µl genomic DNA and 400 pM primers.


View this table:
[in this window]
[in a new window]
  		Table 2. Oligonucleotide Primer Pairs for PCR

 
CSGE
CSGE has been reported to be able to detect essentially all sequence changes.28 29 To make CSGE gels of 300 x 400 x 0.8 mm, 20x TTE buffer containing 1.8 M Tris base, 4 mM EDTA, and 0.6 M taurine (pH 9.0) was prepared.28 29 The gel contained: 2.5x TTE buffer, 37.5 ml acrylamide-bisacrylamide (49:1), 15 ml formamide, 10 ml ethylene glycol, 33 ml water, 0.15% 1,4-bis(acryloyl)piperazine, 0.1% ammonium persulfate, and 70 µl N,N,N',N'-tetramethylethylenediamine (TEMED). The gel was prerun in 0.5x TTE for 30 minutes at 25 W. PCR products were prepared by adding 1:6 volume 6x loading dye containing 0.25% bromophenol blue, 0.25% xylene cyanol, and 30% glycerol, then heating to form heteroduplexes: 98°C for 5 minutes, 68°C for 30 minutes, then at room temperature. After the wells were washed, 5-µl of sample was loaded per well, and a DNA ladder was loaded asymmetrically to help identify the positions of lanes. A positive control known to be heterozygous was run in one lane. Up to three samples were loaded per lane by running the gel at 40 W for 45 minutes between loads. The gel was run at 25 W for approximately 20 hours. The gel was then stained with ethidium bromide, and the DNA bands were visualized and photographed under UV light.

Direct DNA Sequencing
Samples corresponding to bands of altered mobility were sequenced. Sequencing was performed using dRhodamine-labeled terminators on an automated DNA sequencer (model ABI 377; Perkin Elmer).

Restriction Endonuclease Assays
After patients with POAG and family members were screened by CSGE and sequencing, normal controls were screened for the presence of the sequence alterations identified, using restriction endonuclease assays or direct sequencing. Patients with POAG and family members were also screened by restriction analysis to detect any homozygotes not detectable by CSGE. The sequence alterations identified and the restriction enzymes used are listed in Table 3 . One to 5 units of each enzyme were mixed with each sample and incubated with their corresponding buffers overnight at 37°C (except for BsmAI at 55°C). DNA fragments were detected by electrophoresis on 2% agarose or 12% polyacrylamide gels.


View this table:
[in this window]
[in a new window]
  		Table 3. TIGR Sequence Alterations and Restriction Endonuclease Assays

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Ten sequence alterations were identified in our study subjects (Table 4) , of which two were nonsense sequence changes, four were missense changes in encoded amino acid residues, one was a synonymous codon change, and three were changes in noncoding sequences. One of the amino acid sequence changes is novel: Arg91Stop. One sequence change, Gly12Arg, was found only in subjects without glaucoma. Among the sequence alterations that affects an amino acid codon, Arg91Stop was found exclusively in patients with glaucoma, albeit in only one patient (Table 4) .


View this table:
[in this window]
[in a new window]
  		Table 4. Number of Study Subjects with Sequence Alterations Detected in the TIGR Gene

 
In this study, 17 of 91 patients with POAG (19%) and 34 of 132 control subjects (26%) were found to carry a TIGR amino acid sequence variation. Apart from Asp208Glu and Thr353Ile, which are in exons 2 and 3 respectively, the remaining four coding changes—Gly12Arg, Arg46Stop, Arg76Lys, and Arg91Stop—were found to be located in exon 1 (Table 4) .

Arg46Stop was found in only one patient with POAG, P161. He was 4 years of age at the time of diagnosis, with IOP of 35 mm Hg (Table 5) . Six of his family members also carried Arg46Stop, including his mother, three uncles, and two cousins. They did not have glaucoma and were normal in visual acuity and IOP (Table 6) . Arg46Stop was also detected in four unrelated elderly control subjects, all of whom had cataracts but no glaucoma or high IOP (except for a temporary elevation of IOP after cataract surgery in C155). One of them, a 77-year-old woman, was identified as homozygous for Arg46Stop (Fig. 1) . There were four sequence alterations that did not affect encoded amino acids and are unlikely to affect the structure or function of the TIGR protein. Apart from Ala260Ala, which occurred in only 1 POAG index patient, the remaining three—1-83 (G->A) in the promoter, 730 + 35 (A->G) in intron 2, and 1515 + 73 (G->C) in the 3' untranslated region—were found both in patients with POAG and in study subjects without glaucoma (Table 4) . The promoter polymorphism always occurred with the Arg76Lys polymorphism, in subjects with and without POAG.


View this table:
[in this window]
[in a new window]
  		Table 5. Genotype and Clinical Data of Patients with POAG with a Sequence Alteration in the TIGR Gene

 

View this table:
[in this window]
[in a new window]
  		Table 6. Genotype and Clinical Data of Subjects without POAG but with Arg46Stop Mutation in the TIGR Gene

 


View larger version (27K):
[in this window]
[in a new window]
  		Figure 1. Electropherograms resulting from automated sequencing, showing Arg46Stop. (A) Normal sequence, (B) heterozygous sequence, and (C) homozygous sequence.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
One novel amino acid sequence change was discovered in this study: Arg91Stop. However, it was found in only one individual, a patients with POAG. Thus, no conclusion about its effect on disease risk could be made. Four previously published missense changes were found: Gly12Arg, Arg76Lys, Asp208Glu, and Thr353Ile.18 13 30 Thr353Ile was described as a probable glaucoma-causing mutation,18 but it was found in three control subjects in our study (Table 4) . Perhaps the definition of a probable disease-causing mutation should be confined to only the sequence alterations for which a statistically significant increase in frequency is found among patients compared with control subjects. Functional effects of such a mutation should also be confirmed by family linkage analysis and, if possible, in vitro expression studies.

Gly12Arg was found only in subjects without glaucoma. When unrelated control subjects were compared with patients with POAG (Table 3) , there was a trend toward an association of this sequence alteration with the absence of POAG (Fisher’s exact two-tailed test, P = 0.14). Any potential protective effect of Gly12Arg on glaucoma may be confirmed by larger studies among Asian populations in which this sequence alteration occurs.

Arg76Lys was the most common protein sequence polymorphism and displayed no association with POAG. It always occurred with the promoter polymorphism 1-83 (G->A), unlike other ethnic groups.18 That we observed no recombination between these two sequence variants in the cases we screened raises questions about whether any recombination events have occurred in this 309-bp interval since this haplotype entered the Chinese population.

Asp208Glu has been reported only once before, in a Japanese patient with ocular hypertension.30 Although it was also found in two patients with POAG in this study, we cannot conclude whether Asp208Glu contributes to POAG, because it was also found in a 50-year-old normal subject.

However, many sequence alterations in TIGR have been identified that are likely to cause POAG.8 10 13 14 15 16 17 18 19 20 21 22 23 24 25 Table 1 lists the mutations that have been reported in sufficiently large case–control or family studies to give a high likelihood that they are associated with POAG. All are in exon 3, and all but one, Gln368Stop, are missense mutations. There are at least two ways in which TIGR missense mutations may increase IOP: On the one hand, they may act by inactivating a putative normal function of TIGR that keeps IOP from increasing to excessive levels. For example, blockage of TIGR expression has been shown to reduce flow through a cultured TM cell layer.31 On the other hand, the mutations may act by inducing a pathologic activity of the TIGR protein that increases IOP. For example, several of the mutated TIGR species appeared in the insoluble fraction of cultured cells, unlike the normal soluble TIGR.32 A nonsense sequence alteration, Arg46Stop, provides clues to choose the more likely of the above mechanisms.

The Arg46Stop protein truncation is thought to eliminate more than 90% of the normal length of the TIGR protein, with only 13 amino acids remaining after cleavage of the signal sequence.12 Thus, assuming no effects of the sequence change on expression of the normal allele, Arg46Stop essentially reduces TIGR expression by half in heterozygotes, and eliminates expression in homozygotes. Recently, a Korean individual with severe juvenile-onset POAG was found to be homozygous for Arg46Stop.26 However, our Arg46Stop-carrying elderly homozygote, who was 77 years of age, and all but one of our heterozygotes did not have glaucoma, and neither did the heterozygous relatives of the Korean homozygote (although two of them had IOP >=22 mm Hg). Thus, the coexistence of glaucoma with the Arg46Stop sequence in the Korean homozygote may be due to the presence of other genetic or environmental factors interacting with this TIGR alteration. It may be just a coincidence due to two probable factors: Arg46Stop may be common in Asians (3% of our control subjects), and the proportion of patients with glaucoma in those screened for TIGR mutations has been much greater than in the general population. It is tempting to interpret absence of glaucoma in our elderly Arg46Stop homozygote as indicating that loss of TIGR gene product does not cause glaucoma. However, because nonpenetrance has been observed for other clearly pathogenic TIGR mutations, we cannot currently make predictions about whether additional Arg46Stop homozygotes are likely to develop glaucoma. However, these findings suggest that loss of TIGR gene product alone is not enough to result in glaucoma. Thus, these findings raise questions about whether TIGR is essential for normal eye function or whether other proteins can serve the function of TIGR.

Among the 11 Arg46Stop carriers in this study, including the one homozygote identified, only one had high IOP (besides subject C155 after cataract surgery). That Arg46Stop carriers generally do not have high IOP reduces the likelihood that the pressure increase in the presence of missense mutations is the result of the loss of normal TIGR function. Thus, those missense mutations are likely to be creating or enhancing an IOP-increasing function of TIGR. The mechanism by which these mutations lead to increased IOP is not known, but at least two hypotheses appear reasonable: 1) TIGR protein can be secreted by TM cells. It may then contribute to an extracellular matrix that constricts outflow of aqueous humor through the TM. 2) TIGR protein within TM cells may control the structure of the cytoskeleton, affecting the shape of the cells and thus the size of the pores between cells through which aqueous humor may exit. Some mutations may affect binding of TIGR protein to cytoskeleton.

Glucocorticoid treatment increases expression of TIGR by TM cells, and the time course and dose response of this expression are similar to the effect of glucocorticoids on increasing IOP.12 26 If an extracellular mechanism were correct, increased expression of TIGR protein would be expected to increase the probability of TM blockage and increased IOP. The glucocorticoid-induced increases in both TIGR expression and IOP are consistent with this conclusion, although glucocorticoids may increase IOP primarily through other mechanisms.

These observations are also consistent with an intracellular mechanism if increased TIGR protein causes TM cells to change their shape to constrict the pores in the TM. Further study on the effects of intracellular and extracellular TIGR protein will help elucidate the normal and pathologic roles of TIGR.


   Acknowledgements
 
The authors thank Fion Lau for her contribution in contacting subjects and collecting blood samples.


   Footnotes
 
DSCL and CPP contributed equally to the study.

Supported by the Industrial Support Fund, Hong Kong.

Submitted for publication July 14, 1999; revised September 28 and December 7, 1999; accepted December 9, 1999.

Commercial relationships policy: N.

Corresponding author: Chi Pui Pang, Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong University Eye Center, Hong Kong Eye Hospital, 3/F, 147K Argyle Street, Kowloon, Hong Kong. cppang{at}cuhk.edu.hk


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Thylefors, B, Negrel, A. (1994) The global impact of glaucoma World Health Organ Bull Org Monidale Sante 72,323-326
  2. Wilson, R, Martone, J. (1996) Epidemiology of chronic open-angle glaucoma Ritch, R Shields, M Krupin, T eds. The Glaucomas Vol 2,753-768 Mosby St Louis.
  3. Stewart, WC (1995) The effect of lifestyle on the relative risk to develop open-angle glaucoma Curr Opin Ophthalmol 6,3-9[Medline][Order article via Infotrieve]
  4. Wolfs, RCW, Klaver, CW, Ramrattan, RS, van Duijn, CM, Hofman, A, de Jong, PTVM (1998) Genetic risk of primary open angle glaucoma Arch Ophthalmol 116,1640-1645[Abstract/Free Full Text]
  5. Raymond, V. (1997) Molecular genetics of the glaucomas: mapping of the first five "GLC" loci Am J Hum Genet 60,272-277[Medline][Order article via Infotrieve]
  6. Booth, A, Churchill, A, Anwazr, R, Menage, M, Markham, A. (1997) The genetics of primary open angle glaucoma Br J Ophthalmol 81,409-414[Free Full Text]
  7. Wirtz, MK, Samples, JR, Rust, K, et al (1999) GLC1F, a new primary open-angle glaucoma locus, maps to 7q35–q36 Arch Ophthalmol 117,237-241[Abstract/Free Full Text]
  8. Stone, EM, Fingert, JH, Alward, LM, et al (1997) Identification of a gene that causes primary open angle glaucoma Science 275,668-670[Abstract/Free Full Text]
  9. Kubota, R, Noda, S, Wang, Y, et al (1997) A novel myosin-like protein (myocilin) expressed in the connecting cilium of the photoreceptor: molecular cloning, tissue expression, and chromosomal mapping Genomics 41,360-369[Medline][Order article via Infotrieve]
  10. Adam, MF, Belmouden, A, Binisti, P, et al (1997) Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedia-homology domain of TIGR in familial open-angle glaucoma Hum Mol Gen 6,2091-2097[Abstract/Free Full Text]
  11. Kubota, R, Kudoh, J, Mashima, Y, et al (1998) Genomic organization of the human myocilin gene (MYOC) responsible for primary open angle glaucoma Biochem Biophys Res Commun 242,396-400[Medline][Order article via Infotrieve]
  12. Nguyen, TD, Chen, P, Huang, WD, et al (1998) Gene structure and properties of TIGR, an olfactomedin-related glycoprotein cloned from glucorticoid-induced trabecular meshwork cells J Biol Chem 273,6341-6350[Abstract/Free Full Text]
  13. Alward, WLM, Fingert, JH, Coote, MA, et al (1998) Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A) N Engl J Med 338,1022-1027[Abstract/Free Full Text]
  14. Rozsa, FW, Shimizu, S, Lichter, PR, et al (1998) GLC1A mutations point to regions of potential functional importance on the TIGR/MYOC protein Mol Vision 4,20[Medline][Order article via Infotrieve]
  15. Adam, MF, Belmouden, A, Binisti, P, et al (1997) Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma Hum Mol Gen 6,2091-2097
  16. Stoilova, D, Child, A, Brice, G, Crick, RP, Fleck, BW, Sarfarazi, M. (1997) Identification of a new ‘TIGR’ mutation in a family with juvenile-onset primary open angle glaucoma Ophthalmic Genet 18,109-118[Medline][Order article via Infotrieve]
  17. Stoilova, D, Child, A, Brice, G, et al (1998) Novel TIGR/MYOC mutations in families with juvenile onset primary open angle glaucoma J Med Genet 35,989-992[Abstract/Free Full Text]
  18. Fingert, JH, Héon, E, Liebmann, JM, et al (1999) Analysis of myocilin mutations in 1703 glaucoma patients from five different populations Hum Mol Gen 8,899-905[Abstract/Free Full Text]
  19. Allingham, RR, Wiggs, JL, de la Paz, MA, et al (1998) Gln368STOP myocilin mutation in families with late-onset primary open-angle glaucoma Invest Ophthalmol Vis Sci 39,2288-2295[Abstract/Free Full Text]
  20. Suzuki, Y, Shirato, S, Taniguchi, F, Ohara, K, Nishimaki, K, Ohta, S. (1997) Mutations in the TIGR gene in familial primary open-angle glaucoma in Japan Am J Hum Genet 61,1202-1204[Medline][Order article via Infotrieve]
  21. Michels-Rautenstrauss, KG, Mardin, CY, Budde, WM, et al (1998) Juvenile open angle glaucoma: fine mapping of the TIGR gene to 1q24.3-q25.2 and mutation analysis Hum Genet 102,103-106[Medline][Order article via Infotrieve]
  22. Morissette, J, Côté, G, Anctil, JL, et al (1995) A common gene for juvenile and adult-onset primary open-angle glaucomas confined on chromosome 1q Am J Hum Genet 56,1431-1442[Medline][Order article via Infotrieve]
  23. Morissette, J, Clépet, C, Moisan, S, et al (1998) Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma Nat Genet 19,319-321[Medline][Order article via Infotrieve]
  24. Mansergh, FC, Kenna, PF, Ayuso, C, Kiang, AS, Humphries, P, Farrar, GJ (1998) Novel mutations in the TIGR gene in early and late onset open angle glaucoma Hum Mutat 11,244-251[Medline][Order article via Infotrieve]
  25. Richards, JE, Ritch, R, Lichter, PR, et al (1998) Novel trabecular meshwork inducible glucocorticoid response mutation in an eight-generation juvenile-onset primary open-angle glaucoma pedigree Ophthalmology 105,1698-1707[Medline][Order article via Infotrieve]
  26. Yoon, SJK, Kim, HS, Moon, JI, Lim, JM, Joo, CK (1999) Mutations of the TIGR/MYOC gene in primary open-angle glaucoma in Korea Am J Hum Genet 64,1775-1778[Medline][Order article via Infotrieve]
  27. Anderson, DR. (1992) Automated Static Perimetry ,12 Mosby-Year Book St. Louis.
  28. Ganguly, A, Rock, MJ, Prockop, DJ (1993) Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: Evidence for solvent-induced bends in DNA heteroduplexes Proc Natl Acad Sci USA 90,10325-10329[Abstract/Free Full Text]
  29. Körkkö, J, Annunen, S, Pihlajamaa, T, Prockop, DJ, Ala-Kokko, L. (1998) Conformation sensitive gel electrophoresis for simple and accurate detection of mutations: comparison with denaturing gradient gel electrophoresis and nucleotide sequencing Proc Natl Acad Sci USA 95,1681-1685[Abstract/Free Full Text]
  30. Kawase, K, Alward, WLM, Kawase, C, et al (1998) Sequence variation of GLC1A (MYOC/TIGR) gene in Japanese patients with normal-tension glaucoma and ocular hypertension [ARVO abstract] Invest Ophthalmol Vis Sci 40(4),S78Abstract nr 416
  31. Underwood-Hu, JL, Lin, SC, Franse-Carman, I, Alvarado, JA. (1999) ZO-1 and TIGR expression in human trabecular meshwork cells [ARVO abstract] Invest Ophthalmol Vis Sci 40(4),S669Abstract nr 3533
  32. Vollrath, D, Zhou, Z. (1999) A functional assay that distinguishes normal and glaucomatous mutant forms of TIGR/myocilin protein [ARVO abstract] Invest Ophthalmol Vis Sci 40(4),S76Abstract nr 405



This article has been cited by other articles:


Home page
 Mol. Cell. Biol.Home page
H.-S. Kwon, H.-S. Lee, Y. Ji, J. S. Rubin, and S. I. Tomarev
Myocilin Is a Modulator of Wnt Signaling
Mol. Cell. Biol., April 15, 2009; 29(8): 2139 - 2154.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
Y. H. Kwon, J. H. Fingert, M. H. Kuehn, and W. L.M. Alward
Primary Open-Angle Glaucoma
N. Engl. J. Med., March 12, 2009; 360(11): 1113 - 1124.
[Full Text] [PDF]

Home page
 Arch OphthalmolHome page
F. W. Rozsa, K. Scott, H. Pawar, S. Moroi, and J. E. Richards
Effects of Timolol on MYOC, OPTN, and WDR36 RNA Levels
Arch Ophthalmol, January 1, 2008; 126(1): 86 - 93.
[Abstract] [Full Text] [PDF]

Home page
 Arch OphthalmolHome page
A. Bhattacharjee, M. Acharya, A. Mukhopadhyay, S. Mookherjee, D. Banerjee, A. K. Bandopadhyay, S. K. D. Thakur, A. Sen, and K. Ray
Myocilin Variants in Indian Patients With Open-angle Glaucoma
Arch Ophthalmol, June 1, 2007; 125(6): 823 - 829.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
G. H.-F. Yam, K. Gaplovska-Kysela, C. Zuber, and J. Roth
Sodium 4-Phenylbutyrate Acts as a Chemical Chaperone on Misfolded Myocilin to Rescue Cells from Endoplasmic Reticulum Stress and Apoptosis
Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1683 - 1690.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. R. Shepard, N. Jacobson, J. C. Millar, I.-H. Pang, H. T. Steely, C. C. Searby, V. C. Sheffield, E. M. Stone, and A. F. Clark
Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure
Hum. Mol. Genet., March 15, 2007; 16(6): 609 - 617.
[Abstract] [Full Text] [PDF]

Home page
 Arch OphthalmolHome page
J. L. Wiggs
Genetic Etiologies of Glaucoma
Arch Ophthalmol, January 1, 2007; 125(1): 30 - 37.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
G. H.-F. Yam, K. Gaplovska-Kysela, C. Zuber, and J. Roth
Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis: Implications for the Pathogenesis of Myocilin-Caused Primary Open-Angle Glaucoma
Am. J. Pathol., January 1, 2007; 170(1): 100 - 109.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
D. Y. Wang, B. J. Fan, J. K. H. Chua, P. O. S. Tam, C. K. S. Leung, D. S. C. Lam, and C. P. Pang
A Genome-wide Scan Maps a Novel Juvenile-Onset Primary Open-Angle Glaucoma Locus to 15q
Invest. Ophthalmol. Vis. Sci., December 1, 2006; 47(12): 5315 - 5321.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
T. Funayama, Y. Mashima, Y. Ohtake, K. Ishikawa, N. Fuse, N. Yasuda, T. Fukuchi, A. Murakami, Y. Hotta, N. Shimada, et al.
SNPs and Interaction Analyses of Noelin 2, Myocilin, and Optineurin Genes in Japanese Patients with Open-Angle Glaucoma
Invest. Ophthalmol. Vis. Sci., December 1, 2006; 47(12): 5368 - 5375.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
D. B. Gould, M. Reedy, L. A. Wilson, R. S. Smith, R. L. Johnson, and S. W. M. John
Mutant Myocilin Nonsecretion In Vivo Is Not Sufficient To Cause Glaucoma
Mol. Cell. Biol., November 15, 2006; 26(22): 8427 - 8436.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
I. Malyukova, H.-S. Lee, R. N. Fariss, and S. I. Tomarev
Mutated Mouse and Human Myocilins Have Similar Properties and Do Not Block General Secretory Pathway
Invest. Ophthalmol. Vis. Sci., January 1, 2006; 47(1): 206 - 212.
[Abstract] [Full Text] [PDF]

Home page
 Arch OphthalmolHome page
B. J. Fan, D. Y. L. Leung, D. Y. Wang, S. Gobeil, V. Raymond, P. O. S. Tam, D. S. C. Lam, and C. P. Pang
Novel Myocilin Mutation in a Chinese Family With Juvenile-Onset Open-Angle Glaucoma
Arch Ophthalmol, January 1, 2006; 124(1): 102 - 106.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
S. W. M. John
Mechanistic Insights into Glaucoma Provided by Experimental Genetics The Cogan Lecture
Invest. Ophthalmol. Vis. Sci., August 1, 2005; 46(8): 2650 - 2661.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. D. Aroca-Aguilar, F. Sanchez-Sanchez, S. Ghosh, M. Coca-Prados, and J. Escribano
Myocilin Mutations Causing Glaucoma Inhibit the Intracellular Endoproteolytic Cleavage of Myocilin between Amino Acids Arg226 and Ile227
J. Biol. Chem., June 3, 2005; 280(22): 21043 - 21051.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
T. Aung, V. H. K. Yong, P. T. K. Chew, S. K. L. Seah, G. Gazzard, P. J. Foster, and E. N. Vithana
Molecular Analysis of the Myocilin Gene in Chinese Subjects with Chronic Primary-Angle Closure Glaucoma
Invest. Ophthalmol. Vis. Sci., April 1, 2005; 46(4): 1303 - 1306.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
D. B. Gould, L. Miceli-Libby, O. V. Savinova, M. Torrado, S. I. Tomarev, R. S. Smith, and S. W. M. John
Genetically Increasing Myoc Expression Supports a Necessary Pathologic Role of Abnormal Proteins in Glaucoma
Mol. Cell. Biol., October 15, 2004; 24(20): 9019 - 9025.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
S. Gobeil, M.-A. Rodrigue, S. Moisan, T. D. Nguyen, J. R. Polansky, J. Morissette, and V. Raymond
Intracellular Sequestration of Hetero-oligomers Formed by Wild-Type and Glaucoma-Causing Myocilin Mutants
Invest. Ophthalmol. Vis. Sci., October 1, 2004; 45(10): 3560 - 3567.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
R Melki, E Colomb, N Lefort, A P Brezin, and H-J Garchon
CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma
J. Med. Genet., September 1, 2004; 41(9): 647 - 651.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
Y. Liu and D. Vollrath
Reversal of mutant myocilin non-secretion and cell killing: implications for glaucoma
Hum. Mol. Genet., June 1, 2004; 13(11): 1193 - 1204.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
G. Gong, O. Kosoko-Lasaki, G. R. Haynatzki, and M. R. Wilson
Genetic dissection of myocilin glaucoma
Hum. Mol. Genet., April 1, 2004; 13(90001): R91 - 102.
[Abstract] [Full Text] [PDF]

Home page
 Arch OphthalmolHome page
D. S. P. Fan, C. B. O. Yu, T. Y. H. Chiu, C. Y. Wong, J. S. K. Ng, C. P. Pang, and D. S. C. Lam
Ocular-Hypertensive and Anti-inflammatory Response to Rimexolone Therapy in Children
Arch Ophthalmol, December 1, 2003; 121(12): 1716 - 1721.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
Y. F. Leung, B. J. Fan, D. S. C. Lam, W. S. Lee, P. O. S. Tam, J. K. H. Chua, C. C. Y. Tham, J. S. M. Lai, D. S. P. Fan, and C. P. Pang
Different Optineurin Mutation Pattern in Primary Open-Angle Glaucoma
Invest. Ophthalmol. Vis. Sci., September 1, 2003; 44(9): 3880 - 3884.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
S. Sohn, W. Hur, M. K. Joe, J.-H. Kim, Z.-W. Lee, K.-S. Ha, and C. Kee
Expression of Wild-Type and Truncated Myocilins in Trabecular Meshwork Cells: Their Subcellular Localizations and Cytotoxicities
Invest. Ophthalmol. Vis. Sci., December 1, 2002; 43(12): 3680 - 3685.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
C. P. Pang, Y. F. Leung, B. Fan, L. Baum, W. C. Tong, W. S. Lee, J. K. H. Chua, D. S. P. Fan, Y. Liu, and D. S. C. Lam
TIGR/MYOC Gene Sequence Alterations in Individuals with and without Primary Open-Angle Glaucoma
Invest. Ophthalmol. Vis. Sci., October 1, 2002; 43(10): 3231 - 3235.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. Torrado, R. Trivedi, R. Zinovieva, I. Karavanova, and S. I. Tomarev
Optimedin: a novel olfactomedin-related protein that interacts with myocilin
Hum. Mol. Genet., May 16, 2002; 11(11): 1291 - 1301.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
F. Ahmed, M. Torrado, E. Johnson, J. Morrison, and S. I. Tomarev
Changes in mRNA Levels of the Myoc/Tigr Gene in the Rat Eye after Experimental Elevation of Intraocular Pressure or Optic Nerve Transection
Invest. Ophthalmol. Vis. Sci., December 1, 2001; 42(13): 3165 - 3172.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
B. S. Kim, O. V. Savinova, M. V. Reedy, J. Martin, Y. Lun, L. Gan, R. S. Smith, S. I. Tomarev, S. W. M. John, and R. L. Johnson
Targeted Disruption of the Myocilin Gene (Myoc) Suggests that Human Glaucoma-Causing Mutations Are Gain of Function
Mol. Cell. Biol., November 15, 2001; 21(22): 7707 - 7713.
[Abstract] [Full Text] [PDF]

Home page
 Arch OphthalmolHome page
J. L. Wiggs and D. Vollrath
Molecular and Clinical Evaluation of a Patient Hemizygous for TIGR/MYOC
Arch Ophthalmol, November 1, 2001; 119(11): 1674 - 1678.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
N. Jacobson, M. Andrews, A. R. Shepard, D. Nishimura, C. Searby, J. H. Fingert, G. Hageman, R. Mullins, B. L. Davidson, Y. H. Kwon, et al.
Non-secretion of mutant proteins of the glaucoma gene myocilin in cultured trabecular meshwork cells and in aqueous humor
Hum. Mol. Genet., January 1, 2001; 10(2): 117 - 125.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lam, D. S. C.
Right arrow Articles by Pang, C. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lam, D. S. C.
Right arrow Articles by Pang, C. P.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS