Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma

Morissette, Jean; Clépet, Christian; Moisan, Steve; Dubois, Stéphane; Winstall, Éric; Vermeeren, Diana; Nguyen, Thai; Polansky, Jon R.; Côté, Gilles; Anctil, Jean-Louis; Amyot, Marcel; Plante, M.; Falardeau, Pierre; Raymond, Vincent

doi:10.1038/1203

Cited by 106 publications

(65 citation statements)

References 9 publications

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“…In a large pedigree with autosomal-dominant glaucoma caused by a mutation in the MYOC (TIGR) gene, several homozygotes for the mutation were diagnosed by molecular studies among the children of two affected individuals. 9 None of these children had any clinical symptoms of glaucoma. This was significantly different from the expected as observed in the other adult carriers of the mutation in the family when adjusted for age.…”

Section: Autosomal-dominant Glaucomamentioning

confidence: 99%

Penetrance and expressivity in the molecular age

Zlotogora¹

2003

Genetics in Medicine

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Penetrance and expressivity have been defined through clinical experience. Although penetrance is often seen as the end of the spectrum of expressivity, penetrance and expressivity are considered as distinct phenomena. A review of the known mechanisms underlying either penetrance or expressivity reveals that in most of the cases the same explanation is true for both phenomena. Some of the known mechanisms include modifier genes, the influence of the allele in trans, sex, and environmental factors. Although rapid progress has been made in understanding of the basis of incomplete penetrance and the differences of expressivity, they still remain unknown for most of the genetic disorders. In recent years, it has become evident that there is much in common between the classical Mendelian traits in which the inheritance has been seen as "simple" and most of the common diseases in which the inheritance is "complex.

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Section: Autosomal-dominant Glaucomamentioning

confidence: 99%

Penetrance and expressivity in the molecular age

Zlotogora¹

2003

Genetics in Medicine

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“…This leads to endoplasmic reticulum stress and to potential cytotoxicity (16,18,25,26). Although certain molecular mechanisms such as homoallelic complementation, haploinsuffiency, or negative dominant effect have been proposed to explain the pathogenesis of myocilin glaucoma, most experimental evidence supports the gain of function theory (27)(28)(29).…”

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confidence: 99%

Myocilin Mutations Causing Glaucoma Inhibit the Intracellular Endoproteolytic Cleavage of Myocilin between Amino Acids Arg226 and Ile227

Aroca-Aguilar

Sánchez-Sánchez

Ghosh

et al. 2005

Journal of Biological Chemistry

114

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Myocilin is a secreted glycoprotein of unknown function that is ubiquitously expressed in many human organs, including the eye. Mutations in this protein produce glaucoma, a leading cause of blindness worldwide. To explore the biological role of myocilin and the pathogenesis of glaucoma, we have analyzed the expression of recombinant wild type and four representative pathogenic myocilin mutations (E323K, Q368X, P370L, and D380A) in transiently transfected cell lines derived from ocular and nonocular tissues. We found that wild type myocilin undergoes an intracellular endoproteolytic processing at the C terminus of Arg 226. This cleavage predicts the production of two fragments, one of 35 kDa containing the C-terminal olfactomedin-like domain, and another of 20 kDa containing the N-terminal leucine zipper-like domain. Here we have analyzed the 35-kDa processed fragment, and we have found that it is co-secreted with the nonprocessed protein. Western immunoblot analyses showed that human aqueous humor and some ocular tissues also contain the processed 35-kDa myocilin, indicating that the endoproteolytic cleavage occurs in vivo. Mutant myocilins accumulated in the endoplasmic reticulum of transfected cells as insoluble aggregates. Interestingly, the four pathogenic myocilins inhibited the endoproteolytic processing with varying efficiency. Furthermore, the mutation P370L, which produces the most severe glaucoma phenotype, also elicited the most potent endoproteolytic cleavage inhibition. We propose that the endoproteolytic processing might regulate the activity of myocilin and that the inhibition of the processing by pathogenic mutations impairs the normal role of myocilin.

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“…Interestingly, POAG is not induced through genetically increasing or decreasing wild-type MYOC expression [Gould et al, 2004], and people homozygous for disease-causing variants do not necessarily manifest disease [Hewitt et al, 2006a;Morissette et al, 1998]. A gain-of-function disease model was suggested through the observation that mutant forms of the MYOC protein are misfolded and aggregate, akin to Russell body formation, in the endoplasmic reticulum of trabecular meshwork cells [Jacobson et al, 2001;O'Brien et al, 2000;Tamm, 2002;Yam et al, 2007;Zhou and Vollrath, 1999].…”

Section: Introductionmentioning

confidence: 99%

Myocilinallele-specific glaucoma phenotype database

2008

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Communicated by Daniel F. SchorderetGlaucoma, a complex heterogenous disease, is the leading cause for optic nerve-related blindness worldwide.Since 1997, when mutations in the myocilin (MYOC) gene were identified as causing juvenile onset as well as a proportion of primary open-angle glaucoma (POAG), more than 180 variants have been documented. Approximately one in 30 unselected patients with POAG have a disease-causing myocilin mutation and it has been shown that firm genotype-phenotype correlations exist. We have compiled an online catalog of myocilin variants and their associated phenotypes. This locus-specific resource, to which future submissions can be made, is available online (www.myocilin.com; last accessed 28 August 2007). The database, constructed using MySQL, contains three related sheets that contain data pertaining to the information source, variant identified, and relevant study data, respectively. The website contains a list of all identified variants and summary statistics as well as background genomic information, such as the annotated sequence and cross-protein/species homology. Phenotypic data such as the mean7standard deviation (SD) age at POAG diagnosis, mean7SD maximum recorded intraocular pressure, proportion of patients requiring surgical intervention, and age-related penetrance can be viewed by selecting a particular mutation. Approximately 40% of the identified sequence variants have been characterized as disease causing, with the majority (85%) of these being missense mutations. Preliminary data generated from this online resource highlight the strong genotype-phenotype correlations associated with specific myocilin mutations. The large-scale assimilation of relevant data allows for accurate comprehensive genetic counseling and the translation of genomic information into the clinic. Hum Mutat 29(2), [207][208][209][210][211] 2008.

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Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma

Cited by 106 publications

References 9 publications

Penetrance and expressivity in the molecular age

Penetrance and expressivity in the molecular age

Myocilin Mutations Causing Glaucoma Inhibit the Intracellular Endoproteolytic Cleavage of Myocilin between Amino Acids Arg226 and Ile227

Myocilinallele-specific glaucoma phenotype database

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