0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Ophthalmic Molecular Genetics |

Myocilin Gly252Arg Mutation and Glaucoma of Intermediate Severity in Caucasian Individuals FREE

Alex W. Hewitt, MBBS; Sonya L. Bennett, FRANZCO; Julia E. Richards, PhD; David P. Dimasi, BBiotech; Adam P. Booth, FRCOphth, PhD; Chris Inglehearn, PhD; Rashida Anwar, PhD; Tetsuya Yamamoto, MD; John H. Fingert, MD, PhD; Elise Héon, MD; Jamie E. Craig, DPhil, FRANZCO; David A. Mackey, MD, FRANZCO
[+] Author Affiliations

Author Affiliations: Clinical Genetics Unit, Eye Research Australia, University of Melbourne, Royal Victorian Eye & Ear Hospital, Melbourne (Drs Hewitt and Bennett); Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia (Drs Hewitt, Craig, and Mackey, and Mr Dimasi); Department of Ophthalmology, University of Michigan, Ann Arbor (Drs Richards and Booth); Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, England (Drs Booth, Inglehearn, and Anwar); Department of Ophthalmology, Gifu University, Gifu, Japan (Dr Yamamoto); Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City (Dr Fingert); Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario (Dr Héon); and Department of Ophthalmology, University of Tasmania, Royal Hobart Hospital, Hobart, Australia (Dr Mackey).


Section Editor: Janey L. Wiggs, MD, PhD

More Author Information
Arch Ophthalmol. 2007;125(1):98-104. doi:10.1001/archopht.125.1.98.
Text Size: A A A
Published online

Objective  To determine the phenotype of an Australian pedigree with the myocilin (MYOC) Gly252Arg mutation, comparing it with other pedigrees carrying the same mutation.

Methods  All recruited subjects underwent a comprehensive clinical examination, including optic disc assessment, applanation tonometry, and visual field measurement. Mutation analysis was performed through direct sequencing. Haplotype analysis was performed using microsatellite markers around the MYOC gene.

Results  Eight Gly252Arg mutation carriers with glaucoma were identified from the same pedigree. Carriers' mean ± SD age at diagnosis was 46.3 ± 11.4 years (range, 31-60 years). Highest recorded intraocular pressure ranged from 27 to 42 mm Hg (mean ± SD, 32.4 ± 5.6 mm Hg). Cup-disc ratios in the worst eye ranged from 0.6 to 0.9. Six of the 8 individuals had undergone filtration surgery. A common founding haplotype between MY5 and D1S218 was found for Caucasian individuals tested with this mutation. One subject was compound heterozygotic for the MYOC Gly252Arg mutation and a novel MYOC Gly244Val variant.

Conclusions  Although a common founder for Gly252Arg across Caucasian subjects was found, the phenotype from this Australian MYOC mutation–carrying pedigree is less severe than previously described. The severity of glaucoma caused by the Gly252Arg mutation may be similar to the Thr377Met MYOC mutation, yet is more severe than the most common Gln368Stop mutation.

Clinical Relevance  Since its implication in glaucoma, much work has been performed investigating the clinical features of MYOC-related glaucoma. Given the strong genotype-phenotype correlations with MYOC disease-causing variants, health care professionals armed with such molecular information are able to accurately counsel patients on their likely disease course. Our work suggests that the disease associated with MYOC Gly252Arg is less severe than previously described in other pedigrees with this specific mutation.

Figures in this Article

Primary open-angle glaucoma (POAG), the most common form of optic neurodegeneration, is a complex heterogeneous disease.1,2 Understanding the genetic pathoetiological mechanisms for POAG will allow predisease risk stratification as well as the development of novel therapeutic modalities.

The myocilin (MYOC) gene was the first gene in which mutations were found to cause glaucoma.3 Although the precise function of MYOC is unknown, disease-causing mutant forms are relatively detergent insoluble.4 Mutant MYOC proteins are misfolded and retained in the endoplasmic reticulum of the trabecular meshwork cells, while wild-type MYOC is secreted.5 Culturing trabecular meshwork cells at a lower than physiological temperature, a condition known to facilitate protein folding, allows secretion of mutant MYOC and reverses the abnormal morphology and resultant cell lysis. MYOC mutations account for most dominant juvenile glaucoma cases and for approximately 2% to 4% of unselected adult-onset POAG.6,7 Numerous mutations in MYOC have been identified, with the majority of them being clustered in the conserved olfactomedin domain of exon 3.7

Richards and colleagues8 first identified the MYOC Gly252Arg mutation in a Caucasian patient residing in the United States. As described by Shimizu et al,9 this patient was diagnosed with glaucoma at the age of 26 years and had a maximum recorded intraocular pressure (IOP) of 62 mm Hg. In keeping with a juvenile-onset glaucoma phenotype, Booth and colleagues10 described a large Scottish family harboring the MYOC Gly252Arg mutation. The mean ± SD age at POAG diagnosis was approximately 30.8 ± 7.3 years, with a mean ± SD maximum recorded IOP of 39.3 ± 12.5 mm Hg.10 Five of the 6 mutation-carrying individuals who manifested disease had undergone bilateral trabeculectomy.10 Willoughby and colleagues11 have described a 2-generation Chinese pedigree who carried the MYOC Gly252Arg mutation and had juvenile-onset glaucoma. The proband was diagnosed at age 29 years, while her father had been diagnosed at the age of 38 years and had required bilateral trabeculectomy.11 Interestingly, these subjects were also found to have the Arg545Gln variant in optineurin, the second gene identified to cause POAG.11,12 However, this optineurin variant has been found to be distributed equally between Chinese subjects with glaucoma and ethnically matched, normal control subjects and is thus unlikely to be a pathogenetic variant.13 One person of Japanese ethnicity who was given this diagnosis at age 49 years and had a maximum recorded IOP of 40 mm Hg has been identified to have the MYOC Gly252Arg mutation (T.Y., written communication, March 2006).

The MYOC Gly252Arg amino acid substitution is predicted to have a positive charge change and is Triton assay insoluble.9 Herein, we describe the phenotype of an Australian pedigree with the MYOC Gly252Arg mutation and show that all known Caucasian subjects with POAG with this mutation have a common founder.

This study was approved by the ethics committees of the Royal Victorian Eye & Ear Hospital and the Royal Hobart Hospital. It was conducted in accordance with the revised Declaration of Helsinki; written informed consent was provided by each subject. All previously reported subjects were similarly recruited under appropriate approvals and ethical protections.811

Each subject for whom phenotypes were not previously reported underwent a comprehensive clinical examination, which included anterior segment examination, gonioscopy, IOP measurement by Goldmann applanation tonometry, pachymetry, refraction, and a mydriatic optic disc assessment. Simultaneous stereoscopic optic disc photographs were digitalized (Nidek Stereo Fundus Camera 3-Dx/F; Nidek, Gamagori, Japan). All subjects older than 30 years and those younger who had optic disc signs suggestive of glaucomatous damage underwent automated visual field assessment using a computerized perimeter (Humphrey Field Analyzer II; Zeiss-Humphrey, Dublin, Calif).

The Mann-Whitney U test was used to compare the age at diagnosis and maximum recorded IOP among our subjects with POAG and those presented previously by Shimizu et al9 and Booth et al.10 Fisher exact test was used to compare the proportion of subjects who had undergone trabeculectomy in our cohort with that described by Booth et al.10 Statistical analysis was performed using Intercooled Stata 7.0 for Windows (Stata Corp, College Station, Tex).

Genomic DNA was isolated from peripheral blood samples (QIAGEN, Valencia, Calif). The MYOC Gly252Arg mutation was initially detected with the use of single-strand conformation polymorphism analysis. A template of 12.5 ng of DNA was used in an 8.35-μL polymerase chain reaction using primer sequences and conditions previously described.14 Amplified products were denatured and underwent electrophoresis. Subsequent mutation analysis for other members of the family was performed through direct sequencing. The MYOC exon 3 amplicon containing the MYOC 252 codon was amplified.14 The polymerase chain reaction products were purified and directly sequenced (Wizard SV Gel PCR Clean-Up System; Promega Corp, Madison, Wis). Sequencing reactions were carried out using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems, Scoresby, Australia) with 25 cycles of 10 seconds at 95°C and 5 seconds at 50°C, followed by 4 minutes at 60°C, as specified by the manufacturer. Sequencing analysis was performed using a Prism 310 Genetic Analyzer (Applied Biosystems) and was reviewed using Sequencher 4.7 (Gene Codes Corp, Ann Arbor, Mich). To investigate the significance of novel mutations, the coding region of MYOC was fully sequenced in 130 control subjects without glaucoma, who had a mean ± SD age of 81.6 ± 8.6 years.

The haplotype around the MYOC Gly252Arg mutation in affected members of our Australian pedigree was compared with that of subjects with POAG who were known to have the identical mutation. These genotyped individuals comprised 3 pedigrees (North American, Scottish, and Chinese-Canadian families), as well as a single Japanese proband.8,10 Genotyping was performed using 9 microsatellite markers (D1S2658, D1S851, MY5, MY3, D1S2815, D1S1619, D1S218, D1S212, and D1S2640), according to previously described methods.15

The matriarch and patriarch (born circa 1795) for the 6-generation Australian Caucasian pedigree (GACT02) are known to have 85 descendants. Key individuals are shown in Figure 1. Eight subjects from this pedigree with the MYOC Gly252Arg mutation were found to have glaucoma (Table 1). The mean ± SD age at diagnosis was 46.3 ± 11.4 years (range, 31-60 years). Six of these individuals (75%) had undergone filtration surgery. The highest recorded IOP ranged from 27 to 42 mm Hg (mean ± SD, 32.4 ± 5.6 mm Hg). The mean ± SD central corneal thickness was 520 ± 25 μm. Examples of the optic disc and visual field characteristics for these glaucomatous cases are shown in Figure 2.

Place holder to copy figure label and caption
Figure 1.

Principal individuals from the GACT02 pedigree. Individual identification code and year of birth is shown for each symbol. Carrier status of the myocilin Gly252Arg mutation is displayed (+ or −). Note that individual IV:5 is affected by family report.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Optic disc appearance and Humphrey 24-2 visual field findings of subjects with glaucoma carrying the myocilin Gly252Arg mutation.

Graphic Jump Location
Table Graphic Jump LocationTable 1. Clinical Characteristics of Individuals With the MYOC Gly252Arg Mutation

An additional 3 subjects with the MYOC Gly252Arg mutation were diagnosed with ocular hypertension, 2 of whom (subjects V:4 and V:6) had commenced taking a prostaglandin receptor agonist at the age of 40 years. Despite being heterozygous for the Gly252Arg mutation, 3 subjects (subjects IV:20, V:1, and V:2; aged 58, 45, and 39 years, respectively) did not manifest ocular hypertension or have reproducible visual field loss (Figure 3).

Place holder to copy figure label and caption
Figure 3.

Optic disc appearance and Humphrey 24-2 visual field findings of individuals carrying the myocilin Gly252Arg mutation not currently manifesting glaucoma. Note the large optic discs of subject V:1, who has normal intraocular pressures, and that individuals V:4 and V:6 have documented ocular hypertension.

Graphic Jump Location

One affected subject (subject IV:2) was identified as being a compound heterozygote for the MYOC Gly252Arg mutation and a novel MYOC Gly244Val (g.731G>T) variant. Her unaffected brother (subject IV:7) was also found to have this Gly244Val variant. The daughter of subject IV:2 has the MYOC Gly244Val change but not the Gly252Arg mutation and was diagnosed with POAG at age 50 years. The other glaucoma-affected daughter of subject IV:2 declined participation in this study. The MYOC Gly244Val variant was not identified in 260 chromosomes from elderly control subjects without glaucoma.

Phenocopy was identified in 2 branches of the pedigree: in subject IV:1 and the son of subject IV:3 (not shown), and in the granddaughter of subject II:5. Subject IV:1 was diagnosed with glaucoma at age 40 years and had undergone trabeculectomy in both eyes. A great grandniece of subject I:2 (not shown) was diagnosed with glaucoma at age 59 years; however, she was found not to have any MYOC coding sequence mutation. Two individuals (subjects V:4 and V:5) were identified as having a synonymous change at codon 285.

A founding haplotype between MY5 and D1S218 was identified across our pedigree and mutation-carrying Caucasian subjects from Scotland and North America (Table 2).9,10 This haplotype differed from that of the Chinese-Canadian family.11 The precise haplotype around MYOC could not be definitively determined from the Japanese subject.

Table Graphic Jump LocationTable 2. Marker Size for Common Myocilin (MYOC)Mutation Haplotypes

The mean age at onset of glaucoma and ocular hypertension in this Australian pedigree was significantly greater than previously presented (P = .003).9,10 This finding remained significant when the ocular hypertension cases were excluded (P = .01). Maximum recorded IOP and the proportion of subjects requiring trabeculectomy did not significantly differ between our subjects (P = .11 and P = .55, respectively) and those previously described.9,10

We present the phenotype of an Australian pedigree with the MYOC Gly252Arg mutation. The Gly252Arg mutation alters the charge and is predicted to alter the secondary structure of neighboring residues from a β-strand to an α-helix across a conserved motif.18 Further analysis has revealed that the amino acid alteration renders the protein insoluble on Triton solubility assay.9 The MYOC Gly252Arg mutation has not been identified in any normal control series.3,6,9

A common founder across Caucasian subjects with the MYOC Gly252Arg mutation was identified. Evidence of a common ancestry across other MYOC mutations, such as Gln368Stop and Thr377Met, has been described (Table 2).15,16 Such a finding has important implications for future methods discovering other genes or single nucleotide polymorphisms predisposing an individual to adult-onset POAG. For example, a common founding haplotype has been identified with the complement factor H gene Tyr402His allele, which was first implicated in causing a significant proportion of the genetic liability for age-related macular degeneration through case-control association.1921 Given the substantial evidence for a founding haplotype in many MYOC disease-causing variants, it is likely that other POAG-related genes or risk alleles have also arisen from a common founder and thereby may be identified through case-control whole genome association.2

Despite a common founder for this specific MYOC mutation in Caucasian subjects, the phenotype from this Australian Gly252Arg MYOC mutation–carrying pedigree is less severe than previously described. Although a similar proportion required trabeculectomy, the age at diagnosis for glaucoma in our pedigree is significantly older than that described previously in the literature.9,10 Our data suggest that this mutation should be considered in patients with adult-onset glaucoma rather than those solely with juvenile-onset glaucoma and underscore the finding of incomplete penetrance associated with POAG.

From the literature published to date, the Gly252Arg mutation is of comparable glaucoma-causing severity as the MYOC Thr377Met mutation.9,16,22 The Gly252Arg mutation results in a more severe case of the disease than the MYOC Gln368Stop mutation but a less severe case of the disease than other mutations such as Pro370Leu or Lys423Glu.9,2325 Using gonioscopy, Booth and colleagues10 identified abnormal-angle blood vessels or mesodermal tissue remnants in the series of Gly252Arg MYOC–affected subjects they examined. Interestingly, the drainage angle features described by Booth et al10 were not noted in our mutation-carrying patients. Such a difference in angle architecture may be the cause of, or a confounding reason for, the differing age at diagnosis between pedigrees.

The nucleotide change g.731G>T that results in MYOC Gly244Val is caused by a substitution of the first base of exon 3, which is part of the consensus splice acceptor site. Consequently, this variant may cause exon skipping in mutation transcripts. Nonetheless, the novel Gly244Val variant has a Blosum matrix score of −3, implying that natural selection has a low tolerance for this amino acid substitution.26 Codon 244 is relatively well conserved across species (data not shown). Being novel, this variant has not been identified in any control series. It is difficult to decide for certain whether this variant is pathogenic, especially given that an elderly individual carrying it (subject IV:7) was clinically normal, while his niece did manifest the disease at a substantially younger age. Nevertheless, variable penetrance and expressivity is known to occur in MYOC mutations.23 The MYOC compound heterozygote subject was relatively young at diagnosis and had the highest maximum recorded IOP compared with other affected members in the pedigree. The MYOC Gly252Arg mutation is a rare allele of large effect, and the Gly244Val variant may be another rare allele with less substantial but nevertheless significant effect. However, phenotypic variability between related individuals and the single case of a much older, unaffected carrier suggests other, probably common alleles of lesser effect, either at the MYOC or at another locus, and/or the action of some unidentified environmental factor.27

As genetic testing for glaucoma is now more readily available, the differentiation between nonimpairing polymorphisms and disease-causing variants becomes more clinically relevant.28 Clinical outcome studies are required to correlate specific disease-causing variants with the phenotype, thereby bridging the health care professional or genetic counselor to the laboratory.28 Accurate phenotypic descriptions, when compiled with relevant genetic information, should enhance health care professionals' understanding of the specific natural history of individual patients' disease.

Correspondence: David A. Mackey, MD, FRANZCO, Glaucoma Research Unit, Royal Victorian Eye & Ear Hospital, 32 Gisborne St, East Melbourne, Victoria, Australia 3002 (D.Mackey@utas.edu.au).

Submitted for Publication: July 25, 2006; final revision received August 22, 2006; accepted August 22, 2006.

Financial Disclosure: None reported.

Funding/Support: This research was supported by project grant 229960 from the National Health and Medical Research Council (NHMRC); grant EY11671 from the National Eye Institute at the National Institutes of Health; the Jack Brockhoff Foundation; the Ophthalmic Research Institute of Australia; and Glaucoma Australia. Dr Hewitt is supported by an NHMRC Medical Postgraduate Scholarship; Dr Craig is supported in part by an NHMRC Practitioner Fellowship; and Dr Mackey is the recipient of a Pfizer Australia research fellowship.

Acknowledgment: We are grateful for the helpful critique of this manuscript by Douglas Vollrath, MD, PhD.

Resnikoff  SPascolini  DEtya'ale  D  et al.  Global data on visual impairment in the year 2002. Bull World Health Organ 2004;82844- 851
PubMed
Hewitt  AWCraig  JEMackey  DA Complex genetics of complex traits: the case of primary open-angle glaucoma. Clin Experiment Ophthalmol 2006;34472- 484
PubMed Link to Article
Stone  EMFingert  JHAlward  WL  et al.  Identification of a gene that causes primary open angle glaucoma. Science 1997;275668- 670
PubMed Link to Article
Zhou  ZVollrath  D A cellular assay distinguishes normal and mutant TIGR/myocilin protein. Hum Mol Genet 1999;82221- 2228
PubMed Link to Article
Jacobson  NAndrews  MShepard  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;10117- 125
PubMed Link to Article
Fingert  JHHeon  ELiebmann  JM  et al.  Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet 1999;8899- 905
PubMed Link to Article
Fingert  JHStone  EMSheffield  VCAlward  WL Myocilin glaucoma. Surv Ophthalmol 2002;47547- 561
PubMed Link to Article
Richards  JERitch  RLichter  PR  et al.  Novel trabecular meshwork inducible glucocorticoid response mutation in an eight-generation juvenile-onset primary open-angle glaucoma pedigree. Ophthalmology 1998;1051698- 1707
PubMed Link to Article
Shimizu  SLichter  PRJohnson  AT  et al.  Age-dependent prevalence of mutations at the GLC1A locus in primary open-angle glaucoma. Am J Ophthalmol 2000;130165- 177
PubMed Link to Article
Booth  APAnwar  RChen  H  et al.  Genetic screening in a large family with juvenile onset primary open angle glaucoma. Br J Ophthalmol 2000;84722- 726
PubMed Link to Article
Willoughby  CEChan  LLHerd  S  et al.  Defining the pathogenicity of optineurin in juvenile open-angle glaucoma. Invest Ophthalmol Vis Sci 2004;453122- 3130
PubMed Link to Article
Rezaie  TChild  AHitchings  R  et al.  Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 2002;2951077- 1079
PubMed Link to Article
Leung  YFFan  BJLam  DS  et al.  Different optineurin mutation pattern in primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2003;443880- 3884
PubMed Link to Article
Alward  WLFingert  JHCoote  MA  et al.  Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A). N Engl J Med 1998;3381022- 1027
PubMed Link to Article
Baird  PNCraig  JERichardson  AJ  et al.  Analysis of 15 primary open-angle glaucoma families from Australia identifies a founder effect for the Q368STOP mutation of myocilin. Hum Genet 2003;112110- 116
PubMed
Mackey  DAHealey  DLFingert  JH  et al.  Glaucoma phenotype in pedigrees with the myocilin Thr377Met mutation. Arch Ophthalmol 2003;1211172- 1180
PubMed Link to Article
Hewitt  AWBennett  SLDimasi  DPCraig  JEMackey  DA A myocilin Gln368STOP homozygote does not exhibit a more severe glaucoma phenotype than heterozygous cases. Am J Ophthalmol 2006;141402- 403
PubMed Link to Article
Rozsa  FWShimizu  SLichter  PR  et al.  GLC1A mutations point to regions of potential functional importance on the TIGR/MYOC protein. Mol Vis 1998;420
PubMed
Hageman  GSAnderson  DHJohnson  LV  et al.  A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 2005;1027227- 7232
PubMed Link to Article
Haines  JLHauser  MASchmidt  S  et al.  Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308419- 421
PubMed Link to Article
Edwards  AORitter  R  IIIAbel  KJManning  APanhuysen  CFarrer  LA Complement factor H polymorphism and age-related macular degeneration. Science 2005;308421- 424
PubMed Link to Article
Puska  PLemmela  SKristo  PSankila  EMJarvela  I Penetrance and phenotype of the Thr377Met myocilin mutation in a large Finnish family with juvenile- and adult-onset open-angle glaucoma. Ophthalmic Genet 2005;2617- 23
PubMed Link to Article
Craig  JEBaird  PNHealey  DL  et al.  Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier. Ophthalmology 2001;1081607- 1620
PubMed Link to Article
Suzuki  YShirato  STaniguchi  FOhara  KNishimaki  KOhta  S Mutations in the TIGR gene in familial primary open-angle glaucoma in Japan. Am J Hum Genet 1997;611202- 1204
PubMed Link to Article
Morissette  JClepet  CMoisan  S  et al.  Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma. Nat Genet 1998;19319- 321
PubMed Link to Article
Henikoff  SHenikoff  JG Amino acid substitution matrices from protein blocks. Proc Natl Acad Sci U S A 1992;8910915- 10919
PubMed Link to Article
Petersen  MBKitsos  GSamples  JR  et al.  A large GLC1C Greek family with a myocilin T377M mutation: inheritance and phenotypic variability. Invest Ophthalmol Vis Sci 2006;47620- 625
PubMed Link to Article
Stone  EM Finding and interpreting genetic variations that are important to ophthalmologists. Trans Am Ophthalmol Soc 2003;101437- 484
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Principal individuals from the GACT02 pedigree. Individual identification code and year of birth is shown for each symbol. Carrier status of the myocilin Gly252Arg mutation is displayed (+ or −). Note that individual IV:5 is affected by family report.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Optic disc appearance and Humphrey 24-2 visual field findings of subjects with glaucoma carrying the myocilin Gly252Arg mutation.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Optic disc appearance and Humphrey 24-2 visual field findings of individuals carrying the myocilin Gly252Arg mutation not currently manifesting glaucoma. Note the large optic discs of subject V:1, who has normal intraocular pressures, and that individuals V:4 and V:6 have documented ocular hypertension.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Clinical Characteristics of Individuals With the MYOC Gly252Arg Mutation
Table Graphic Jump LocationTable 2. Marker Size for Common Myocilin (MYOC)Mutation Haplotypes

References

Resnikoff  SPascolini  DEtya'ale  D  et al.  Global data on visual impairment in the year 2002. Bull World Health Organ 2004;82844- 851
PubMed
Hewitt  AWCraig  JEMackey  DA Complex genetics of complex traits: the case of primary open-angle glaucoma. Clin Experiment Ophthalmol 2006;34472- 484
PubMed Link to Article
Stone  EMFingert  JHAlward  WL  et al.  Identification of a gene that causes primary open angle glaucoma. Science 1997;275668- 670
PubMed Link to Article
Zhou  ZVollrath  D A cellular assay distinguishes normal and mutant TIGR/myocilin protein. Hum Mol Genet 1999;82221- 2228
PubMed Link to Article
Jacobson  NAndrews  MShepard  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;10117- 125
PubMed Link to Article
Fingert  JHHeon  ELiebmann  JM  et al.  Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet 1999;8899- 905
PubMed Link to Article
Fingert  JHStone  EMSheffield  VCAlward  WL Myocilin glaucoma. Surv Ophthalmol 2002;47547- 561
PubMed Link to Article
Richards  JERitch  RLichter  PR  et al.  Novel trabecular meshwork inducible glucocorticoid response mutation in an eight-generation juvenile-onset primary open-angle glaucoma pedigree. Ophthalmology 1998;1051698- 1707
PubMed Link to Article
Shimizu  SLichter  PRJohnson  AT  et al.  Age-dependent prevalence of mutations at the GLC1A locus in primary open-angle glaucoma. Am J Ophthalmol 2000;130165- 177
PubMed Link to Article
Booth  APAnwar  RChen  H  et al.  Genetic screening in a large family with juvenile onset primary open angle glaucoma. Br J Ophthalmol 2000;84722- 726
PubMed Link to Article
Willoughby  CEChan  LLHerd  S  et al.  Defining the pathogenicity of optineurin in juvenile open-angle glaucoma. Invest Ophthalmol Vis Sci 2004;453122- 3130
PubMed Link to Article
Rezaie  TChild  AHitchings  R  et al.  Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 2002;2951077- 1079
PubMed Link to Article
Leung  YFFan  BJLam  DS  et al.  Different optineurin mutation pattern in primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2003;443880- 3884
PubMed Link to Article
Alward  WLFingert  JHCoote  MA  et al.  Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A). N Engl J Med 1998;3381022- 1027
PubMed Link to Article
Baird  PNCraig  JERichardson  AJ  et al.  Analysis of 15 primary open-angle glaucoma families from Australia identifies a founder effect for the Q368STOP mutation of myocilin. Hum Genet 2003;112110- 116
PubMed
Mackey  DAHealey  DLFingert  JH  et al.  Glaucoma phenotype in pedigrees with the myocilin Thr377Met mutation. Arch Ophthalmol 2003;1211172- 1180
PubMed Link to Article
Hewitt  AWBennett  SLDimasi  DPCraig  JEMackey  DA A myocilin Gln368STOP homozygote does not exhibit a more severe glaucoma phenotype than heterozygous cases. Am J Ophthalmol 2006;141402- 403
PubMed Link to Article
Rozsa  FWShimizu  SLichter  PR  et al.  GLC1A mutations point to regions of potential functional importance on the TIGR/MYOC protein. Mol Vis 1998;420
PubMed
Hageman  GSAnderson  DHJohnson  LV  et al.  A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 2005;1027227- 7232
PubMed Link to Article
Haines  JLHauser  MASchmidt  S  et al.  Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308419- 421
PubMed Link to Article
Edwards  AORitter  R  IIIAbel  KJManning  APanhuysen  CFarrer  LA Complement factor H polymorphism and age-related macular degeneration. Science 2005;308421- 424
PubMed Link to Article
Puska  PLemmela  SKristo  PSankila  EMJarvela  I Penetrance and phenotype of the Thr377Met myocilin mutation in a large Finnish family with juvenile- and adult-onset open-angle glaucoma. Ophthalmic Genet 2005;2617- 23
PubMed Link to Article
Craig  JEBaird  PNHealey  DL  et al.  Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier. Ophthalmology 2001;1081607- 1620
PubMed Link to Article
Suzuki  YShirato  STaniguchi  FOhara  KNishimaki  KOhta  S Mutations in the TIGR gene in familial primary open-angle glaucoma in Japan. Am J Hum Genet 1997;611202- 1204
PubMed Link to Article
Morissette  JClepet  CMoisan  S  et al.  Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma. Nat Genet 1998;19319- 321
PubMed Link to Article
Henikoff  SHenikoff  JG Amino acid substitution matrices from protein blocks. Proc Natl Acad Sci U S A 1992;8910915- 10919
PubMed Link to Article
Petersen  MBKitsos  GSamples  JR  et al.  A large GLC1C Greek family with a myocilin T377M mutation: inheritance and phenotypic variability. Invest Ophthalmol Vis Sci 2006;47620- 625
PubMed Link to Article
Stone  EM Finding and interpreting genetic variations that are important to ophthalmologists. Trans Am Ophthalmol Soc 2003;101437- 484
PubMed

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 6

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles