Myocilin Glaucoma Fingert, John H; Stone, Edwin M; Sheffield, Val C ...
Survey of ophthalmology,
11/2002, Letnik:
47, Številka:
6
Journal Article
Recenzirano
Genetic factors have long been implicated in the pathophysiology of primary open-angle glaucoma (POAG). Recently, myocilin, a gene of unknown function, was associated with both juvenile open-angle ...glaucoma (JOAG) and POAG. Forty-three different myocilin mutations have been reported in open-angle glaucoma patients, and several large studies have suggested that as a group these mutations are associated with 3–4% of POAG in patient populations worldwide. Support for the pathogenicity of the individual myocilin mutations has been obtained from in vitro assays, statistical methods, and conservation of gene sequence arguments. Several of these myocilin mutations were observed in multiple patients allowing the identification of mutation-specific glaucoma phenotypes (maximum intraocular pressure and age at diagnosis). Associations between myocilin and other forms of open-angle glaucoma have been explored. At present there is no evidence to link myocilin mutations and steroid-induced ocular hypertension or normal-tension glaucoma. Clinical vignettes of POAG patients from four generations of a family harboring the TYR437HIS myocilin mutation are presented, highlighting the benefits of elucidating the genetics of glaucoma.
Expressed sequence tags (ESTs) have provided a first glimpse of the collection of transcribed sequences in a variety of organisms. However, a careful analysis of this sequence data can provide ...significant additional functional, structural and evolutionary information. Our analysis of the public EST sequences, available through the TIGR Gene Indices (TGI; http://www.tigr.org/tdb/tdb.html ), is an attempt to identify the genes represented by that data and to provide additional information regarding those genes. Gene Indices are constructed for selected organisms by first clustering, then assembling EST and annotated gene sequences from GenBank. This process produces a set of unique, high-fidelity virtual transcripts, or tentative consensus (TC) sequences. The TC sequences can be used to provide putative genes with functional annotation, to link the transcripts to mapping and genomic sequence data, and to provide links between orthologous and paralogous genes.
The use of biological and synthetic meshes to aid implant coverage in implant-based breast reconstruction is well established. This technique allows single stage implant-based reconstruction compared ...to the traditional technique which required tissue expansion before permanent implant placement and therefore involved two operations for the patient. They can further be used for pre-pectoral implant reconstructions in a similar direct-to-implant strategy. This retrospective observational study by Pompei et al has evaluated the use of TIGR Matrix, a long-term resorbable mesh, in 49 patients with 60 operated breasts for both reconstructive and aesthetic cases. They have reported their operative method and followed up their cases for a mean of 12 months. They have reported a cumulative mesh complication rate of 5.4% and one implant was explanted due to infection. They identified a significant correlation between obesity and mesh-related complications. This study is significant as there remains little data regarding the long term outcomes of resorbable synthetic mesh for breast reconstruction. Their reported complication rates are consistent with those in other studies for synthetic meshes. As synthetic meshes can be significantly cheaper than their biological counterparts, this work could promote more widespread use.
Many clinical and fundamental studies have shown that high myopia (HM) and glaucoma are closely associated. In particular, the occurrence and progression of primary open‐angle glaucoma interact with ...the progression of HM. Two hypotheses have been proposed to explain the association between the two disorders: the hypertension gene theory and the collagen‐related gene theory. HM and primary open‐angle glaucoma patients show similar collagen changes and hypersensitive responses to glucocorticoids. Consequently, these common features may hold key information regarding their underlying mechanisms. Advances in life sciences, such as molecular genetics, provide opportunities for clarifying their association at the molecular level. This article reviews available research on the association between these two disorders from the perspectives of epidemiology, clinical manifestation, diagnosis and pathogenic mechanisms.
TIGR/MYOC mutations account for 2–4% of the primary open-angle glaucoma (POAG) patients. More than 90% of the known mutations are located within its carboxy-terminus olfactomedin-homology (Olf) ...domain (amino acids (aa) 245–504). In vitro and in vivo studies showed that several Olf domain mutations prevented myocilin secretion. To investigate if intracellular sequestration was a characteristic feature shared by a majority of the mutations, we analyzed the secretion status of 36 myocilin variants. These encompassed 26 glaucoma-causing mutations and 10 non-disease associated or undefined polymorphisms. As several variants were found to be secreted, we tested for their adhesion to the extracellular matrix (ECM) and/or cell surface.
Myocilin variants were generated by site-directed mutagenesis of a vector encoding the human
MYOC cDNA. COS-7 or immortalized human trabecular meshwork cells were transfected with wild-type or mutated
MYOC constructs. Myocilin levels were estimated by immunoprecipitation and/or immunoblotting. All variants showed identical behaviors in both cell lines; the truncated R46X polypeptide being the only variant which could not be detected in our assays. Of the 35 variants monitored, 20 remained sequestered intracellularly. All of them encoded disease-causing polypeptides carrying Olf domain mutations. Of the 15 variants secreted into the culture medium, six (6) were POAG mutants (of which three (3) located within the Olf domain) while the remaining nine (9) were non-disease causing or undefined polymorphisms. Three (3) of the six (6) secreted mutations caused familial POAG; these were the R126W, T377M and A427T mutants. Both, the T377M and A427T mutants located within the Olf domain. When cells were cultured at 30
°C, a process known to facilitate protein folding, 11 of the 20 sequestered mutants were released in the extracellular medium. Out of the 15 secreted variants tested for their adhesion to the ECM and/or cell surface, only the R82C and L95P polypeptides displayed loss of their adhesive properties. Deletion experiments revealed that the coiled-coil (aa 78–105) and leucine zipper (aa 114–183) motifs were essential for adhesion. These experiments demonstrate that intracellular sequestration might be the primary mechanism contributing to myocilin-related POAG as it was associated with more than 80% of the disease-causing mutants tested in our study. A second mechanism may involve abnormal interaction(s) between myocilin and ECM and/or cell surface proteins. Our data further revealed the importance of the olfactomedin-homology domain for myocilin secretion and the significant role of the N-terminal region for its extracellular interactions.
Potato (
Solanum tuberosum
L.) tubers are an excellent staple food due to its high nutritional value. When the tuber reaches physiological competence, sprouting proceeds accompanied by changes at ...mRNA and protein levels. Potato tubers become a source of carbon and energy until sprouts are capable of independent growth. Transcript profiling of sprouts grown under continuous light or dark conditions was performed using the TIGR 10K EST Solanaceae microarray. The profiles analyzed show a core of highly expressed transcripts that are associated to the reactivation of growth. Under light conditions, the photosynthetic machinery was fully activated; the highest up-regulation was observed for the Rubisco activase (RCA), the glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and the Photosystem II 22 kDa protein (CP22) genes, among others. On the other hand, sprouts exposed to continuous darkness elongate longer, and after extended darkness, synthesis of chloroplast components was repressed, the expression of proteases was reduced while genes encoding cysteine protease inhibitors (CPIs) and metallocarboxypeptidase inhibitors (MPIs) were strongly induced. Northern blot and RT-PCR analysis confirmed that MPI levels correlated with the length of the dark period; however, CPI expression was strong only after longer periods of darkness, suggesting a feedback loop (regulation mechanism) in response to dark-induced senescence. Prevention of cysteine protease activity in etiolated sprouts exposed to extended darkness could delay senescence until they emerge to light.
Cytokinins have been implicated in delaying leaf senescence. We previously generated transgenic cotton (
Gossypium hirsutum
L.) plants that harbor the
Agrobacterium
isopentenyl transferase gene (
ipt
...) directed by a proteinase gene promoter. Here, we report that mRNAs were isolated from
ipt
cotton leaves and azygous leaves and were subsequently sequenced using
Illumina Solexa
technology. The sequence tags were searched against the
TIGR
database and the related gene expression profiles were compared resulting in the identification of 1 218 differentially expressed genes (DEGs): 719 up-regulated and 499 down-regulated. Analyzing the DEGs in the
ipt
cotton leaves showed that these genes belonged to four pathways: flavone biosynthesis, arginine and proline metabolism, glyoxylate and dicarboxylate metabolism, and RNA degradation. These pathways increased the activities of antioxidants, inhibited the effect of ethylene, and prevented degradation of macromolecules during senescence. The expression patterns of 17 genes were evaluated by real-time PCR and results were in agreement with the patterns of sequencing analysis. The identification of the DEGs may help us to understand a role of cytokinins in leaf senescence.
Accurate surface temperature retrieval using thermal infrared observations from satellites is important for surface energy balance modeling; however it is difficult to achieve without proper ...correction for atmospheric effects. Typically the atmospheric correction is obtained from radiosonde profiles and a radiative transfer model (RTM). But rigorous RTM processing is impractical for routine continental scale modeling because of long computational times. An alternative, simpler, and faster approach for correcting observations in the 10–12.5 μm band is developed from a previously published water vapor continuum absorption function. Using the RTM program MODTRAN as a reference, the function is calibrated against 159 radiosondes, and then validated against the TIGR radiosonde (1761 profiles) data set. Implementation of the calibrated absorption function usually produced larger temperature corrections than without calibration, an effect due to water vapor band type absorption and to non-water vapor constituents. The resulting surface temperature estimates, within 0.8 °C of MODTRAN estimates, were achieved at 15× less processing time than MODTRAN.
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