Trabecular Meshwork Inducible Glucocorticoid Response Protein Research Articles

English

Myocilin (OMIM601652) MYOC gene, first revealed as a protein isolated from cultured human Trabecular Meshwork (TM) cells after prolong dexame thasone treatment. Hence given the name TIGR (Trabecular Meshwork Inducible Glucocorticoid Response Protein). The human myocilin gene, a concealed acidic glycoprotein,contains 504 amino acids, positioned at chromosome 1(1q24.3 ‐ 1q25.2), and filled with olfactomedin do main at its C terminus. Myocilin exists in various tissues throughout the eye and many other organs. M utant myocilin cause endoplasmic reticulum pressure in eye angle tissues, including the trabec ular meshwork, damaging the cells inside the meshwork, ultimately leading to structural changes in the outflow pathway, and high intraocular pressure.TM is vital in controlling pressure and mu tations in MYOC.It has been recognized as the cause of juvenile and adult onset of primary open a ngle glaucoma.

Study on MYOC/TIGR gene mutations in primary open-angle glaucoma

To study the mutations in the trabecular meshwork induced-glucocorticoid response protein gene (TIGR/MYOC) in Chinese POAG patients. It was a case-control study. One hundred and eighteen Chinese patients with POAG and 150 control subjects without POAG were screened for coding sequence of the MYOC gene by polymerase chain reaction, single-strand conformation polymorphism (SSCP) and DNA sequence. Restriction endonuclease analysis was used to detect the SSCP in 150 gender- and aged-matched controls. Statistical significance of the difference in frequencies of MYOC mutations between POAG patients and the controls was determined by the chi-squared test. Three coding sequence variants that lead to amino acid changes were identified in MYOC gene. One mutation of MYOC gene was novel, I288M, which was present in one patient with POAG and 3 control subjects. G12R and Y353I have been reported previously. I288M and Y353I were found in both the subjects with and without POAG, the difference of the frequency of these two mutations between POAG and the controls was χ(2) = 0.07, P = 0.791 and χ(2) = 0.56, P = 0.453, respectively. Coding sequence mutations of MYOC were found in 4.23% POAG patients. Frequency of G12R mutation in POAG patients was significantly greater than that in the controls (χ(2) = 4.37, P = 0.037). One novel variant locus in the MYOC/TIGR (I288M) was found in the present study, but this mutation is not associated with POAG. G12R is the most common mutation in MYOC locus in Chinese subjects with POAG. Approximately 4.23% sporadic POAG patients have mutation in the exon 1 in MYOC/TIGR.

A Multidomain TIGR/Olfactomedin Protein Family with Conserved Structural Similarity in the N-terminal Region and Conserved Motifs in the C-terminal Region

Based on the similarity between the TIGR (trabecular-meshwork inducible glucocorticoid response) (also known as myocilin) and olfactomedin protein families identified throughout the length of the TIGR protein, we have identified more distantly related proteins to determine the elements essential to the function/structure of the TIGR and olfactomedin proteins. Using a sequence walk method and the Shotgun program, we have identified a family including 31 olfactomedin domain-containing sequences. Multiple sequence alignments and secondary structure analyses were used to identify conserved sequence elements. Pairwise identity in the olfactomedin domain ranges from 8 to 64%, with an average pairwise identity of 24%. The N-terminal regions of the proteins fall into two subgroups, one including the TIGR and olfactomedin families and another group of apparently unrelated domains. The TIGR and olfactomedin sequences display conserved motifs including a residual leucine zipper region and maintain a similar secondary structure throughout the N-terminal region. The correlation between conserved elements and disease-associated mutations and apparent polymorphisms in human TIGR was also examined to evaluate the apparent importance of conserved residues to the function/structure of TIGR. Several residues have been identified as essential to the function and/or structure of the human TIGR protein based on their degree of conservation across the family and their implication in the pathogenesis of primary open-angle glaucoma. Additionally, we have identified a group of chitinase sequences containing several of the highly conserved motifs present in the C-terminal region of the olfactomedin domain-containing sequences.

Hunting for disease genes in multi-functional diseases.

Disease genes may be identified through functional, positional, and candidate gene approaches. Although extensive and often labor-intensive studies such as family linkage analysis, functional investigation of gene products and genome database searches are usually involved, thousands of human disease genes, especially for monogenic diseases with Mendelian transmission, have been identified. However, in diseases caused by more than one gene, or by a combination of genetic and environmental factors, identification of the genes is even more difficult. Common examples include atherosclerosis, cancer, Alzheimer's disease, asthma, diabetes, glaucoma, and age-related macular degeneration. There have been conflicting reports on the roles of associated genes. Even with population-based case-control studies and new statistical methods such as the sib-ship disequilibrium test and the discordant alleles test, there is no agreement on whether alpha2-macroglobulin (A2M) is a gene for Alzheimer's disease. Another example is the inconsistent association between age-related macular degeneration and ATP-binding cassette transporter (ABCR). Ethnic variation causes further complications. In our investigation of LDL-receptor variants in familial hypercholesterolemia, and the trabecular meshwork inducible glucocorticoid response protein, or myocillin (TIGR-MYOC) mutation pattern in primary open angle glaucoma, we did find dissimilar results in Chinese compared to Caucasians. New information from the Human Genome Project and advancements in technologies will aid the search for and confirm identification of disease genes despite such challenges.

Age-dependent prevalence of mutations at the GLC1A locus in primary open-angle glaucoma

PURPOSE: To screen a population with primary open-angle glaucoma for mutations in the gene that encodes the trabecular meshwork inducible glucocorticoid response protein (TIGR), also known as myocilin (MYOC). METHODS: Ophthalmologic information was collected for study subjects with primary open-angle glaucoma and their relatives. Mutation screening of 74 primary open-angle glaucoma probands was conducted by sequencing TIGR/MYOC coding sequence and splice sites. RESULTS: In 23 families we detected 13 nonsynonymous sequence changes, nine of which appear to be mutations likely to cause or contribute to primary open-angle glaucoma. Two mutations, Arg272Gly and Ile499Ser, and one nonsynonymous sequence variant, Asn57Asp, are novel. We found mutations in nine of 25 juvenile glaucoma probands (36%) and two of 49 adult-onset glaucoma probands (4%). Age classification of families rather than individual probands revealed mutations in three of nine families with strictly juvenile primary open-angle glaucoma (33%), and no mutations in 39 families with strictly adult-onset primary open-angle glaucoma (0%). In families with mixed-onset primary open-angle glaucoma containing both juvenile primary open-angle glaucoma and adult-onset primary open-angle glaucoma cases, we found mutations in eight of 26 families (31%). CONCLUSIONS: Our data suggest that Gly252Arg, Arg272Gly, Glu323Lys, Gln368STOP, Pro370Leu, Thr377Met, Val426Phe, Ile477Asn, and Ile499Ser are likely to play roles that cause or contribute to the etiology of autosomal dominant primary open-angle glaucoma. Our finding of more TIGR/MYOC mutations in families with mixed-onset primary open-angle glaucoma than in the families with strictly adult-onset primary open-angle glaucoma implies that the presence of relatives with juvenile primary open-angle glaucoma in a family could be used as a basis for identifying a subset of the population with adult-onset primary open-angle glaucoma with higher prevalence of TIGR/MYOC mutations. To address this issue, and to refine estimations of mutation prevalence in these age-defined subpopulations, prospective study of a larger population ascertained entirely through adult-onset primary open-angle glaucoma probands will be needed.

The myocilin (MYOC) gene expression in the human trabecular meshwork

Purpose. We previously reported a novel cytoskeletal protein with a myosin-like domain which is localized in the ciliary rootlet and basal body of connecting cilium of photoreceptor and hence we named it ‘myocilin’. It was soon realized that myocilin is identical to a protein called TIGR (trabecular meshwork inducible glucocorticoid response protein) which was found to be responsible for the pathogenesis of juvenile open angle glaucoma. In this study, we employed in situ RNA hybridization to examine the myocilin (MYOC)/ TIGR gene expression in the trabecular meshworks of glaucomatous and nonglaucomatous eyes. Methods. The glaucomatous specimens were obtained by trabeculectomy from the patients with primary open angle glaucoma (POAG), chronic angle closure glaucoma (CACG) and steroid glaucoma, respectively, and the nonglaucomatous specimens were obtained from a victim of traffic accident at autopsy and from a patient with maxillary sinus carcinoma at enucleation for the operation. The in situ RNA hybridization was carried out with digoxigenin-labeled sense and antisense RNA probes. Results. In all cases, hybridization signals were detected primarily in the trabecular meshwork cells and secondarily in the fibroblast-like cells of corneoscleral wall. Conclusions. Myocilin gene is expressed clearly in the trabecular meshwork cells of both glaucomatous and nonglaucomatous eyes.

Detection of a New TIGR Gene Mutation in a Japanese Family With Primary Open Angle Glaucoma

Purpose: To describe a new mutation of the trabecular meshwork-inducible glucocorticoid response protein (TIGR) gene in a Japanese patient with familial primary open angle glaucoma (POAG). Methods: Standard ocular examinations were performed on the 44-year-old patient, his sister, and mother. DNA sequencing was used to identify the mutation. We also developed a DNA diagnostic method for detecting this missense mutation by polymerase chain reaction-induced mutation restriction analysis (PCR-IMRA). Results: The patient, father, and sister had been diagnosed as having POAG. The patient and his sister had a Thr448Pro mutation (C→A transition at the nucleotide number 1419) in exon 3. This mutation has not been reported before. Conclusions: Gene analysis is promising for an early diagnosis among the family members of familial POAG patients and will contribute to early therapy before an occurrence of irreversible visual impairment.

Novel TIGR/MYOC mutations in families with juvenile onset primary open angle glaucoma.

Mutations in the trabecular meshwork induced glucocorticoid response protein (TIGR) or myocilin (MYOC) has recently been shown to cause juvenile onset primary open angle glaucoma (JOAG). In this study, we...

Novel mutations in the TIGR gene in early and late onset open angle glaucoma.

A gene for juvenile onset, open angle glaucoma (JOAG) has been localized to chromosome 1q21-31 in several families. Mutations in the trabecular meshwork-induced glucocorticoid response protein (TIGR) gene, which maps to this region, recently have been found in families segregating both JOAG and a later onset form of primary open angle glaucoma (POAG). We have analysed the TIGR gene in two families; one Spanish family segregating autosomal dominant JOAG and an Irish family with a later onset form of autosomal dominant POAG. We have found a G-T transversion in the first base of codon 426 in all affected members of the Spanish family, which results in a valine to phenylalanine amino acid substitution. We have also found a G-A transition at the first base of codon 367 that segregates through all but one branch of the Irish family and results in a glycine to arginine amino acid substitution. Members of this family that carry the Gly367Arg change also share a common haplotype that is neither present in any of the unaffected members of the family, nor in the branch that does not segregate the mutation. Identification of further mutations in the TIGR gene increases its importance in the etiology of open angle glaucoma.

Novel mutations in the TIGR gene in early and late onset open angle glaucoma

A gene for juvenile onset, open angle glaucoma (JOAG) has been localized to chromosome 1q21-31 in several families. Mutations in the trabecular meshwork-induced glucocorticoid response protein (TIGR) gene, which maps to this region, recently have been found in families segregating both JOAG and a later onset form of primary open angle glaucoma (POAG). We have analysed the TIGR gene in two families; one Spanish family segregating autosomal dominant JOAG and an Irish family with a later onset form of autosomal dominant POAG. We have found a G-T transversion in the first base of codon 426 in all affected members of the Spanish family, which results in a valine to phenylalanine amino acid substitution. We have also found a G-A transition at the first base of codon 367 that segregates through all but one branch of the Irish family and results in a glycine to arginine amino acid substitution. Members of this family that carry the Gly367Arg change also share a common haplotype that is neither present in any of the unaffected members of the family, nor in the branch that does not segregate the mutation. Identification of further mutations in the TIGR gene increases its importance in the etiology of open angle glaucoma. Hum Mutat 11:244–251, 1998. © 1998 Wiley-Liss, Inc.

Recent advances in molecular genetics of glaucomas.

Glaucomas are a heterogeneous group of eye conditions with manifestation from as early as birth to very late age of onset in life. The primary type of these conditions affecting children and juveniles are less frequent, but the prevalence of glaucomas affecting older people of > or = 70 years progressively rises to approximately 5%. The molecular genetics of three types of glaucoma have been the subject of investigation in the last few years. As a result, two loci (GLC3A and GLC3B) have been identified for primary congenital glaucoma, one locus (GLC1A) for juvenile-onset primary open angle glaucoma and a further two loci (GLC1B and GLC1C) for late-onset chronic open angle glaucoma. Early this year, the first set of mutations was described in the CYP1B1 (Cytochrome P4501B1) and TIGR (Trabecular meshwork Inducible Glucocorticoid Response Protein) genes for the GLC3A and GLC1A-linked families, respectively. The mapping of different types of glaucoma and mutation identification in these two genes are the focus of this review.