Characterization and Comparison of the Human and Mouse<i>GLC1A</i> Glaucoma Genes

Fingert, John H.; Ying, Lihua; Swiderski, Ruth E.; Nystuen, Arne; Arbour, Nancy C.; Alward, Wallace L.M.; Sheffield, Val C.; Stone, Edwin M.

doi:10.1101/gr.8.4.377

Cited by 99 publications

(59 citation statements)

References 15 publications

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“…Despite a broad expression pattern (1,2,7,(11)(12)(13), the function of MYOC remains unknown and its cellular distribution ambiguous. For example, MYOC has been observed in various cell types to associate with structures that are part of the secretory pathway, including endoplasmic reticulum, Golgi apparatus, and intracellular vesicles.…”

Section: Myocilin (Myoc)mentioning

confidence: 99%

Extracellular Trafficking of Myocilin in Human Trabecular Meshwork Cells

Hardy¹,

Hoffman

González

et al. 2005

Journal of Biological Chemistry

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Myocilin (MYOC) is a protein with a broad expression pattern, but unknown function. MYOC associates with intracellular structures that are consistent with secretory vesicles, however, in most cell types studied, MYOC is limited to the intracellular compartment. In the trabecular meshwork, MYOC associates with intracellular vesicles, but is also found in the extracellular space. The purpose of the present study was to better understand the mechanism of extracellular transport of MYOC in trabecular meshwork cells. Using a biochemical approach, we found that MYOC localizes intracellularly to both the cytosolic and particulate fractions. When intracellular membranes were separated over a linear sucrose gradient, MYOC equilibrated in a fraction less dense than traditional secretory vesicles and lysosomes. In pulse-labeling experiments that followed nascent MYOC over time, the characteristic doublet observed for MYOC by SDS-PAGE did not change, even in the presence of brefeldin A; indicating that MYOC is not glycosylated and is not released via a traditional secretory mechanism. When conditioned media from human trabecular meshwork cells were examined, both native and recombinant MYOC associated with an extracellular membrane population having biochemical characteristics of exosomes, and containing the major histocompatibility complex class II antigen, HLA-DR. The association of MYOC with exosome-like membranes appeared to be specific, on the extracellular face, and reversible. Taken together, data suggest that MYOC appears in the extracellular space of trabecular meshwork cells by an unconventional mechanism, likely associated with exosome-like vesicles. Myocilin (MYOC),1 also known as trabecular meshwork inducible glucocorticoid response protein, is an acidic 504-amino acid protein. Structurally, MYOC contains at least two folding domains, an N-terminal coiled-coil and a C-terminal globular domain with significant homology to an olfactomedin module present in several different proteins (1, 2). Mammalian proteins with the olfactomedin module localize to different compartments of the secretory pathway, although little is known about the function of these proteins or the olfactomedin module (3-10).Despite a broad expression pattern (1, 2, 7, 11-13), the function of MYOC remains unknown and its cellular distribution ambiguous. For example, MYOC has been observed in various cell types to associate with structures that are part of the secretory pathway, including endoplasmic reticulum, Golgi apparatus, and intracellular vesicles. Conversely, MYOC has also been reported to associate with mitochondria and cytoplasmic filaments (11, 14 -17). Even more unusual, MYOC appears to be secreted by some cell types, but not by others (2, 18). Thus, MYOC is expressed by retinal ganglion cells, photoreceptors, and retinal pigment epithelium, but is not found extracellularly in the retina nor in conditioned medium of retinal pigment cells in culture (2,18,19). In contrast, MYOC is found in conditioned medium of trabecular meshwork (TM) ...

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Section: Myocilin (Myoc)mentioning

confidence: 99%

Extracellular Trafficking of Myocilin in Human Trabecular Meshwork Cells

Hardy¹,

Hoffman

González

et al. 2005

Journal of Biological Chemistry

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“…It is now well established that mutations in the myocilin (MYOC) gene may lead to glaucoma and are found in more than 10% of juvenile open angle glaucoma cases and in 3-4% of patients with adult onset primary open angle glaucoma (7)(8)(9)(10). Glaucoma is one of the leading causes of irreversible blindness in the world.…”

mentioning

confidence: 99%

Myocilin Interacts with Syntrophins and Is Member of Dystrophin-associated Protein Complex

Margetis

Kee

Tomarev

2012

Journal of Biological Chemistry

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Background:The non-ocular function(s) of myocilin, a glaucoma-associated protein, is not known. Results: Myocilin interacts with syntrophin, a component of dystrophin-associated protein complex (DAPC) and increases phosphorylation of several regulators of muscle size. Conclusion: Myocilin is involved in the muscle hypertrophy pathways acting through the components of DAPC. Significance: This is the first demonstration of myocilin functions in the skeletal muscles.

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“…Comparison of the genomic structure of mouse and human IA-2 shows that both species have 23 exons and like many mammalian genes [20,21] show very similar intron-exon junctions (Fig. 3).…”

Section: Discussionmentioning

confidence: 99%

Genomic structure of mouse IA-2 : comparison with its human homologue

2000

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The protein tyrosine phosphatase-like molecule IA-2 is a new member of the transmembrane protein tyrosine phosphatase (PTP) family [1,2]. It is distantly related to other transmembrane PTPs with 35±40 % sequence similarity in the intracellular domain. It is also closely related to another new member of the transmembrane PTP family, IA-2b, with 74 % identity in the intracellular domain [3,4]. Human IA-2 and mouse IA-2 are, however, very closely related to each other showing 98 % identity in the intracellular domain and 92 % identity in the extracellular domain [5]. Although IA-2 is a member of the PTP family based on sequence analysis, it lacks enzymatic activity with conventional PTP substrates [2].Over the last few years IA-2 has generated considerable interest because it was found to be a major autoantigen in Type I (insulin-dependent) diabetes mellitus [6±12]. Approximately 70 % of pateints with newly diagnosed Type I diabetes have autoantibodies to IA-2. These autoantibodies appear years before the development of clinical disease and, thus, serve Abstract Aims/hypothesis. IA-2 is a transmembrane protein with a tyrosine phosphatase (PTP)-like structure and a major autoantigen in Type I (insulin-dependent) diabetes mellitus. Because the nucleotide sequence of human and mouse IA-2 cDNA are closely related, it seemed likely that the genomic organization of the two molecules would be similar. To test this possibility the current experiments were initiated to characterize and compare the genomic structure of mouse and human IA-2. Methods. IA-2 cDNA was used to screen a 129SVJ mouse genomic library. We selected and mapped 7 overlapping clones. The subcloned inserts were used to determine intron-exon junctions by direct sequencing. Polymerase chain reaction and restriction mapping were used to estimate the size of the introns. Results. The mouse IA-2 gene and the 5' upstream regulatory region were isolated and the intron-exon junctions determined. Mouse IA-2 encompasses approximately 20 kb and encodes 23 exons. Both the 3' and 5' ends were mapped by rapid amplification of cDNA ends (RACE) and a 2 kb 5'-upstream region was shown to have functional promoter activity. Conclusion/interpretation. Comparison of the genomic structure of mouse and human IA-2 shows that they have the same number of exons and nearly identical intron-exon junctions. The region around the major transcription start site of mouse IA-2 is similar to human IA-2 and other transmembrane protein tyrosine phosphatases. It is concluded that human and mouse IA-2 are highly conserved and derived from a common ancestral gene. [Diabetologia (2000) 43: 1429±1434] Keywords IA-2, insulin-dependent diabetes mellitus, autoantibodies, genomic structure, protein tyrosine phosphatase, intron-exon junctions.

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Characterization and Comparison of the Human and MouseGLC1A Glaucoma Genes

Cited by 99 publications

References 15 publications

Extracellular Trafficking of Myocilin in Human Trabecular Meshwork Cells

Extracellular Trafficking of Myocilin in Human Trabecular Meshwork Cells

Myocilin Interacts with Syntrophins and Is Member of Dystrophin-associated Protein Complex

Genomic structure of mouse IA-2 : comparison with its human homologue

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