A Common Disease Haplotype for the Q368STOP Mutation of the Myocilin Gene in Australian and Canadian Glaucoma Families

doi:10.1016/j.ajo.2005.04.043

American Journal of Ophthalmology

Volume 140, Issue 4, October 2005, Pages 760-762

https://doi.org/10.1016/j.ajo.2005.04.043 Get rights and content

Purpose

To ascertain whether there is a common disease haplotype for the Q368STOP mutation of the myocilin gene in Australian and Canadian families with primary open-angle glaucoma (POAG).

Design

Family pedigree study.

Methods

A disease haplotype for the Q368STOP mutation of the myocilin gene has previously been identified in 15 Tasmanian families with POAG. The four microsatellite markers that constitute this 0.14-megabase (Mb) disease haplotype were genotyped in individuals from a large French Canadian family with POAG (family CT) and two unrelated French Canadian individuals with ocular hypertension.

Results

The Tasmanian Q368STOP disease haplotype was identified in affected individuals from family CT, and the same alleles were shared at the four microsatellite markers in the two unrelated French Canadian individuals.

Conclusion

The same disease haplotype for the Q368STOP mutation of the myocilin gene was found in both the Tasmanian and French Canadian populations, supporting the view that this mutation arose from a common Caucasian founder.

References (7)

J.M. Tielsch et al.
Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey
JAMA
(1991)
E.M. Stone et al.
Identification of a gene that causes primary open angle glaucoma
Science
(1997)
J.H. Fingert et al.
Analysis of myocilin mutations in 1703 glaucoma patients from five different populations
Hum Mol Genet
(1999)

There are more references available in the full text version of this article.

Cited by (12)

Novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation
2024, Cell Reports Medicine
Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of which were ancestry specific. Gene-enrichment and transcriptome-wide association analyses implicate vascular and cancer genes, a fifth of which are primary ciliary related. We perform an extensive statistical analysis of SIX6 and CDKN2B-AS1 loci in human GTEx data and across large electronic health records showing interaction between SIX6 gene and causal variants in the chr9p21.3 locus, with expression effect on CDKN2A/B. Our results suggest that some POAG risk variants may be ancestry specific, sex specific, or both, and support the contribution of genes involved in programmed cell death in POAG pathogenesis.
Evaluation of the Myocilin Mutation Gln368Stop Demonstrates Reduced Penetrance for Glaucoma in European Populations
2017, Ophthalmology
Sequence variations in the myocilin (MYOC) gene account for approximately 2% to 4% of glaucoma cases. One particular MYOC mutation, Gln368Stop (dbSNP accession number: rs74315329), is the most common genetic mutation causing glaucoma by increasing intraocular pressure (IOP). The objective of this study was to evaluate the effect of this MYOC mutation on IOP using data from large-scale European population panels (directly sequenced and imputation based).
Cross-sectional, cohort study.
For this study, the penetrance of the variant rs74315329 was estimated in 2 population-based cohorts, the TwinsUK (N = 6092) and the Rotterdam Study (RS) (N =11 189).
Carriers of the risk allele for rs74315329 were identified using whole-genome sequencing and imputation data (based on 1000 Genomes Project and Haplotype Reference Consortium panels). The penetrance of this variant was evaluated using IOP measurements and data on visual field testing/a diagnosis of glaucoma (if available).
The penetrance of the variant rs74315329 was estimated from the percentage of the carriers of the risk allele of the variant who had high IOP (ocular hypertension) or glaucoma.
In our study, the observed penetrance of the variant rs74315329 in relation to increased IOP was 12.5% and 19.4% in the TwinsUK and the RS, respectively. Thus, our study suggests a much lower penetrance for rs74315329 for ocular hypertension (and thus glaucoma), in comparison with that reported previously.
The significance of this finding is that higher numbers of healthy individuals in the population are expected to be carriers of this mutation, which in turn reduces the utility of identifying carriers of this mutation as a screening tool for glaucoma.
Higher prevalence of myocilin mutations in advanced glaucoma in comparison with less advanced disease in an australasian disease registry
2013, Ophthalmology
Citation Excerpt :
This was a population-based study, which means that some participants may be from the same family. The authors previously reported that the Myocilin Gln368X mutation has a common genetic origin, even when ascertained in unrelated Australian and Canadian families.44,47 As a result, all patients carrying Gln368X mutation in fact are distantly related.
To determine the proportion of all Myocilin coding mutations responsible for advanced primary open-angle glaucoma (POAG) in early-age-at-onset individuals and to investigate the prevalence of exon 3 Myocilin mutations in advanced POAG at any age at onset in a large Australasian cohort.
Cross-sectional study using a national disease registry.
One thousand sixty individuals with advanced POAG (103 with age at onset of 40 years or younger) and 320 with nonadvanced POAG all recruited by the Australian and New Zealand Registry of Advanced Glaucoma.
Participants were examined and referred by their eye practitioner, and Myocilin genetic testing was performed by direct sequencing. Cascade genetic testing was made available for relatives of participants found to carry a Myocilin mutation.
Advanced glaucoma diagnosis based on strict visual field entry criteria. Prevalence and spectrum of Myocilin mutations in individuals with advanced and nonadvanced POAG.
This is the first study to report Myocilin mutations in an advanced POAG cohort. No pathogenic Myocilin mutations were identified in exons 1 and 2 in early-age-at-onset advanced POAG cases. Exon 3 Myocilin mutations were identified in 45 advanced POAG patients (4.2%), which is significantly higher (P = 0.02) compared with nonadvanced POAG patients (1.6%). A novel mutation (Trp373X) and a new variant of uncertain pathogenicity (Ala447Thr) also were reported. The prevalence of Myocilin mutations rose from 16% to 40% in selected advanced POAG subgroups based on different thresholds of maximum recorded intraocular pressure, age at diagnosis, and the presence and strength of positive family history. Twenty-six individuals with Myocilin mutations were identified through cascade genetic testing of first-degree relatives of affected mutation carriers.
The prevalence of Myocilin mutations in glaucoma cases with severe visual field loss is significantly greater than in nonadvanced glaucoma patients. Myocilin screening in phenotypically selected cases can have a much higher yield than in previous unselected series. Identifying individuals who have Myocilin mutations provides an opportunity to screen at-risk clinically unaffected relatives and to reduce glaucoma blindness through early management and intervention.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Accurate imputation-based screening of Gln368Ter myocilin variant in primary open-angle glaucoma
2015, Investigative Ophthalmology and Visual Science
Genetic eye research in Tasmania: A historical overview
2012, Clinical and Experimental Ophthalmology
Primary open angle glaucoma due to T377M MYOC: Population mapping of a Greek founder mutation in Northwestern Greece
2010, Clinical Ophthalmology

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: This work was supported by grant 128202 from the National Health and Medical Research Council of Australia; grant MOP-64219 from the Canadian Institutes of Health Research; the Fonds de la Recherche en Santé du Québec (FRSQ) Vision Research Network; and the estate of Dorothy Edols.

¹: Dr Vincent Raymond is an FRSQ National Investigator.

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Brief reportA Common Disease Haplotype for the Q368STOP Mutation of the Myocilin Gene in Australian and Canadian Glaucoma Families

Purpose

Design

Methods

Results

Conclusion

Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey

JAMA

Identification of a gene that causes primary open angle glaucoma

Science

Analysis of myocilin mutations in 1703 glaucoma patients from five different populations

Hum Mol Genet

Brief report
A Common Disease Haplotype for the Q368STOP Mutation of the Myocilin Gene in Australian and Canadian Glaucoma Families