UMLS:C0595921 - FACTA Search

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Query: UMLS:C0595921 (intraocular pressure)
11,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

According to a recent epidemiological study done in Japan, 2 or 3 million Japanese people are thought to be suffering from glaucoma, and 70-80% of them have not been examined or diagnosed by ophthalmologists. Therefore, the problem is how to find these untreated and undiagnosed people. At present, treatment of glaucoma continues to be directed at lowering intraocular pressure to prevent progression of glaucomatous optic neuropathy. However, theoretically, there are three stages in the prevention of progression of glaucoma. In the first stage, diagnosis of glaucoma can be done by genetic examination, before occurrence of glaucoma. The MYOCILIN/trabecular meshwork-inducible glucocorticoid response gene and the optineurin gene were identified as the genes that cause open angle glaucoma. Although some Japanese patients have sequence changes in the myocilin gene, there are no apparent specific mutations in Japanese glaucoma patients, in the MYOCILIN/TIGR and optineurin genes. Secondary glaucoma such as steroid glaucoma, induced by allergic diseases, and neovascular glaucoma, induced by retinal circulatory insufficiency, are preventable by improving the causal diseases, diabetes and hypertension. The education of doctors and laymen is important to reduce the occurrence of diabetes, and hypertension to prevent diabetic retinopathy, and retinal vessel occlusion. The second stage in preventing progression of glaucoma is to find the disease as early as possible. In Japan, a physical examination system is in place for everybody over 40 years old, in companies and local districts. Therefore, ocular examination, specially non-mydriatic fundus photographs should be taken in these examinations, and the film should be evaluated by an ophthalmologist, to search for retinal and optic disc abnormalities. Primary open angle glaucoma can be detected through this system in early stages. In primary angle closure glaucoma, instruments for estimating anterior chamber rapidly and accurately are necessary for the diagnosis. There is a special machine which can be handled easily, safely, and economically for detecting angle closure glaucoma, has been developed by Yamanashi University. This machine might help to reduce the number of angle closure glaucoma patients in the world. In the near future, a glaucoma network system should be put in place all over Japan. This organization consists of central headquarter and local central office. Most hospitals and private offices will belong to a local central office, and several glaucoma specialists will work in central and local offices. All glaucoma patients will be registered in local glaucoma office. The information on glaucoma patients will be communicated in the system the through light fiber cables or a satellite system. The patients can ask about their own disease through this glaucoma center system. In the third stage of glaucoma prevention, progression of glaucomatous optic neuropathy is retarded by conventional IOP lowering treatment or neuroprotective drugs. This stage compromises rehabilitation of visual function, implant of artificial visual systems, and regeneration of retinal ganglion cells(RGC). The disturbances of axonal flow in guinea pig optic nerve fibers was demonstrated electromicroscopically by quick-freeze, deep-etching method and, the decrease in numbers of motor proteins like "Kinesin" "Dynein" and "MAP-1" was shown in guinea pig eyes with elevated intraocular pressure by immunohistochemistry. Retinal glanglion cells have been isolated and new findings have been reported using this RGC culture system. Therefore, new neuroprotective drugs will be developed through this culture system.
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PMID:[21st century management of glaucoma]. 1473 29

Human diseases develop by complex mutual relationships of genetic and environmental factors. In inherited diseases, DNA diagnosis of the disease-causing genes provides a confirmation of the disease. On the other hand, DNA diagnosis of the disease-sensitive genes in multifactorial diseases, such as the lifestyle-related diseases (common diseases), provides the risk of developing the disease. Two new technologies are being used for DNA diagnosis in the clinic. The first is called Invader Technology and is a non-PCR method and is useful for detecting well-known genetic variations in large samples efficiently. We have developed a method to quantify the heteroplasmy of mitochondrial DNA mutations by this technique. The second technique, called WAVE, uses denaturing high-performance liquid chromatography to screen for mutations in a large number of samples automatically and efficiently. Clinical DNA diagnoses are divided into those for single genetic diseases and those for multifactorial diseases. The purposes for DNA diagnosis in single genetic diseases are: 1) to propose a new clinical classification of the disease, such as TGFB1-related corneal dystrophy or retinitis pigmentosa, based on the genotypes; 2) to confirm a clinical diagnosis, such as Leber's hereditary optic neuropathy (LHON); and 3) to provide an early diagnosis before the development of the disease and thus provide an opportunity to start early treatment. For example, a family history of glaucoma is one of the risk factors for developing glaucoma. The frequency of mutations in the glaucoma genes, myocilin and optineurin, were found to be about 3% and 0.25%, respectively, in Japanese. The significance of DNA diagnosis in multifactorial diseases is that it provides a risk diagnosis for an individual. Single nucleotide polymorphisms (SNPs) of disease-sensitive genes are associated with only a 2- to 3-fold risk of developing the disease. A case-control association study was performed using many SNP markers to identify glaucoma-sensitive genes. A total of 671 Japanese individuals, 201 POAG patients, 234 NTG patients, and 236 normal controls were examined. Fifty-two SNPs in the 38 genes were examined to identify the glaucoma-sensitive genes as candidate genes, and SNPs in AT 1, AT 2, PON 1, GSTT 1, NOS 3, and EDN 1 were associated with glaucoma statistically. Mitochondrial (mt) DNA mutations associated with LHON might be risk factors for open-angle glaucoma, because abnormal optic disc excavations are also found in LHON patients. A total of 651 blood samples were screened for 6 LHON-associated mutations with the Invader assay. Seven patients had one of the five mutations, but none had developed LHON. The 5 mutations were not identified in 236 normal controls. MtDNA mutations may make the optic disc more susceptible to damage in glaucoma patients. The clinical variability in LHON patients suggests that the disease most likely results from multi factorial mechanisms. To determine whether genetic polymorphisms for oxidative stress and apoptosis cause clinical variability in patients with LHON, 12 polymorphisms in 10 genes were analyzed in 87 patients with the 11778 mutation in relation to the age at onset and final visual acuity. LHON patients carrying homozygous His 113 in the EPHX1 gene or homozygous Arg 72 in the TP53 gene developed the disease earlier than those without this genotype. Thus, nuclear genetic polymorphisms related to oxidative stress or apoptosis may modify the age of LHON onset. A clinical trial of 38 healthy volunteers without systemic diseases or eye diseases was performed using an angiotensin II receptor blocker (candesartan cilexetil) as an alternative drug for lowering intraocular pressure (IOP). After a single oral dose of candesartan cilexetil, the IOP fell significantly for 24 hr. There was no association between the effects of oral candesartan cilexetil and the three SNPs in the AT 1 gene. In the 21th century, DNA diagnosis for multifactorial diseases will be required to determine the treatment plan for individuals or to prevent diseases. We have developed a panel of tests by Invader assay for clinical use to detect mutations in the myocilin gene or in LHON. In the future, we will develop a panel to detect SNPs in the glaucoma-sensitive genes to diagnose individuals at risk for developing glaucoma. Such information is expected to help develop new medications.
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PMID:[DNA diagnosis in the age of individual made-to-order medications]. 1565 90

A collection of DNA samples obtained from primary open-angle glaucoma (POAG) patients from St. Petersburg was analyzed for single-strand conformation polymorphism (SSCP) to reveal sequence variants in exon 3 of the myocilin gene (MYOC/TIGR) and in exons 4 and 5 of the optineurin gene (OPTN), where most of the mutations revealed worldwide are located. The Q368X mutation (c. 1102 C --> T) in exon 3 of MYOC/TIGR was detected in 1.2% (2/170) of the POAG patients from St. Petersburg, i.e., with the frequency close to that observed in other world populations. Three known polymorphisms in exon 3 of MYOC/TIGR, Y347Y (c. 1041 T --> C) (12.4%), T325T (c. 975 G --> A) (0.6%), and K398R (c. 1193 A --> G) (0.6%) were also detected. No statistically significant differences in frequencies of these polymorphisms were revealed between the POAG patient and control groups. The L41L polymorphism (c. 433 G --> A) in exon 4 of OPTN was detected in 2.9% of probands and in 1% of controls. The frequency of heterozygotes for the M98K polymorphism (c. 603 T --> A) in the OPTN exon 5 was statistically significantly higher (P = 0.036; Fisher's exact test) among the POAG patients (6.5%) than among the controls (1%). In the sample examined the E50K mutation, typical of the patients with pseudonormal intraocular pressure glaucoma, was not found.
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PMID:[Mutations and polymorphisms in the genes for myocilin and optineur in as the risk factors of primary open-angle glaucoma]. 1635 25

To what extent do postmitotic neurons regulate gene expression during development or after injury? We took advantage of our ability to highly purify retinal ganglion cells (RGCs) to profile their pattern of gene expression at 13 ages from embryonic day 17 through postnatal day 21. We found that a large proportion of RGC genes are regulated dramatically throughout their postmitotic development, although the genes regulated through development in vivo generally are not regulated similarly by RGCs allowed to age in vitro. Interestingly, we found that genes regulated by developing RGCs are not generally correlated with genes regulated in RGCs stimulated to regenerate their axons. We unexpectedly found three genes associated with glaucoma, optineurin, cochlin, and CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1), previously thought to be primarily expressed in the trabecular meshwork, which are highly expressed by RGCs and regulated through their development. We also identified several other RGC genes that are encoded by loci linked to glaucoma. The expression of glaucoma-linked genes by RGCs suggests that, at least in some cases, RGCs may be directly involved in glaucoma pathogenesis rather than indirectly involved in response to increased intraocular pressure. Consistent with this hypothesis, we found that CYP1B1 overexpression potentiates RGC survival.
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PMID:Disease gene candidates revealed by expression profiling of retinal ganglion cell development. 1768 37

Glaucoma is one of the leading causes of bilateral blindness affecting nearly 8 million people worldwide. Glaucoma is characterized by a progressive loss of retinal ganglion cells (RGCs) and is often associated with elevated intraocular pressure (IOP). However, patients with normal tension glaucoma (NTG), a subtype of primary open-angle glaucoma (POAG), develop the disease without IOP elevation. The molecular pathways leading to the pathology of NTG and POAG are still unclear. Here, we describe the phenotypic characteristics of transgenic mice overexpressing wild-type (Wt) or mutated optineurin (Optn). Mutations E50K, H486R and Optn with a deletion of the first (amino acids 153-174) or second (amino acids 426-461) leucine zipper were used for overexpression. After 16 months, histological abnormalities were exclusively observed in the retina of E50K mutant mice with loss of RGCs and connecting synapses in the peripheral retina leading to a thinning of the nerve fiber layer at the optic nerve head at normal IOP. E50K mice also showed massive apoptosis and degeneration of entire retina, leading to approximately a 28% reduction of the retina thickness. At the molecular level, introduction of the E50K mutation disrupts the interaction between Optn and Rab8 GTPase, a protein involved in the regulation of vesicle transport from Golgi to plasma membrane. Wt Optn and an active GTP-bound form of Rab8 complex were localized at the Golgi complex. These data suggest that alternation of the Optn sequence can initiate significant retinal degeneration in mice.
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PMID:Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice. 2038 42

Coding variants in both myocilin (MYOC) and optineurin (OPTN) are reported risk factors for primary open-angle glaucoma (POAG) in many populations. This study investigated the contribution of MYOC and OPTN coding variants in Hispanics of Mexican descent with and without POAG. We conducted a case-control study of unrelated POAG cases and nonglaucomatous controls in a population of Hispanics of Mexican descent. Ascertainment criteria for POAG included the presence of glaucomatous optic neuropathy with associated visual field loss and the absence of secondary causes of glaucoma. Controls had normal optic nerves, visual fields and intraocular pressure. All coding exons of MYOC and OPTN were sequenced. The data set consisted of 88 POAG cases and 93 controls. A novel nonsynonymous coding variant (R7H) in the first exon of MYOC was identified. Other identified variants in MYOC and OPTN have been previously described and do not seem to contribute to POAG risk. This is the first comprehensive study of MYOC and OPTN in Hispanics of Mexican descent with POAG. Neither MYOC nor OPTN sequence variants seem to have a major role in the etiology of POAG in this population.
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PMID:Myocilin and optineurin coding variants in Hispanics of Mexican descent with POAG. 2066 60

Although the majority of patients with glaucoma have elevated intraocular pressure as the presumed etiology for their resultant neuropathy, it is well known that approximately 25% of patients with glaucoma have intraocular pressure within the normal range for their race. These patients may have conditions that facilitate non-pressure related stress to the retina and optic nerve that might directly contribute to their glaucomatous neuropathy and include chronic or intermittent ischemia (i.e atherosclerosis, heart disease, vasospasm, migraine, sleep apnea), altered scleral/optic nerve head morphology that predisposes to glaucomatous stress (i.e myopia); genetic mutations that predispose to glaucoma damage at normal IOP (OPA-1,optineurin, myocilin) and evidence of aberrant immunity that suggests that their glaucoma might be a form of an autoimmune neuropathy (i.e. presumed autoimmune glaucoma). This review provides a critical assessment of the potential role for autoimmunity as an initiating or exacerbating etiology in some patients with glaucoma.
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PMID:The case for autoimmunity in glaucoma. 2080 Nov 14

Loss of vision and visual impairment due to glaucoma can be prevented or delayed, if the disease is detected at an early stage. The most important risk factors for open-angle glaucoma include age, elevated intraocular pressure, exfoliation of the lens, i.e. exfoliation syndrome, and genetic factors. To date, genetic studies on glaucoma have revealed more than 20 gene loci and three candidate genes, myocilin (MYOC), optineurin (OPTN) and WD repeat domain 36 (WDR36). A mutation in both the MYOC and WDR36 genes has been found in Finnish families.
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PMID:[Current status of genome research on open-angle glaucoma in Finland]. 2188 43

Glaucoma is the leading cause for blindness affecting 60 million people worldwide. The optineurin (OPTN) E50K mutation was first identified in familial primary open-angle glaucoma (POAG), the onset of which is not associated with intraocular pressure (IOP) elevation, and is classified as normal-tension glaucoma (NTG). Optineurin (OPTN) is a multifunctional protein and its mutations are associated with neurodegenerative diseases such as POAG and amyotrophic lateral sclerosis (ALS). We have previously described an E50K mutation-carrying transgenic (E50K-tg) mouse that exhibited glaucomatous phenotypes of decreased retinal ganglion cells (RGCs) and surrounding cell death at normal IOP. Further phenotypic analysis of these mice revealed persistent reactive gliosis and E50K mutant protein deposits in the outer plexiform layer (OPL). Over-expression of E50K in HEK293 cells indicated accumulation of insoluble OPTN in the endoplasmic reticulum (ER). This phenomenon was consistent with the results seen in neurons derived from induced pluripotent stem cells (iPSCs) from E50K mutation-carrying NTG patients. The E50K mutant strongly interacted with TANK-binding kinase 1 (TBK1), which prohibited the proper oligomerization and solubility of OPTN, both of which are important for OPTN intracellular transition. Treatment with a TBK1 inhibitor, BX795, abrogated the aberrant insolubility of the E50K mutant. Here, we delineated the intracellular dynamics of the endogenous E50K mutant protein for the first time and demonstrated how this mutation causes OPTN insolubility, in association with TBK1, to evoke POAG.
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PMID:Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma. 2366 51

Glaucoma is the most common cause of irreversible blindness worldwide. One subset of glaucoma, normal tension glaucoma (NTG) occurs in the absence of high intraocular pressure. Mutations in two genes, optineurin (OPTN) and TANK binding kinase 1 (TBK1), cause familial NTG and have known roles in the catabolic cellular process autophagy. TKB1 encodes a kinase that phosphorylates OPTN, an autophagy receptor, which ultimately activates autophagy. The sequestosome (SQSTM1) gene also encodes an autophagy receptor and also is a target of TBK1 phosphorylation. Consequently, we hypothesized that mutations in SQSTM1 may also cause NTG. We tested this hypothesis by searching for glaucoma-causing mutations in a cohort of NTG patients (n = 308) and matched controls (n = 157) using Sanger sequencing. An additional 1098 population control samples were also analyzed using whole exome sequencing. A total of 17 non-synonymous mutations were detected which were not significantly skewed between cases and controls when analyzed separately, or as a group (p > 0.05). These data suggest that SQSTM1 mutations are not a common cause of NTG.
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PMID:SQSTM1 Mutations and Glaucoma. 2727 41

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