Biomedical subjects

Tayebeh Rezaie

Publications and source records attributed to Tayebeh Rezaie.

7 recordsLinked to original sources

PubMed2005

Molecular cloning, genomic structure, and protein characterization of mouse optineurin.

We recently identified optineurin (OPTN) as a novel gene for glaucoma and determined its mRNA and protein expression patterns in different human tissues. Herein, we describe the cloning, mapping, genomic organization, and mRNA and protein expression patterns for murine optineurin (Optn). We mapped Optn to chromosome 2, within a region that is syntenic to human 10p14. Optn has 13 coding exons and its exon-intron boundaries are evolutionarily conserved with human. Optn encodes an 884-amino-acid protein and shows 78% identity to OPTN. Northern blot analysis revealed three mRNA transcripts with highest expression in adult liver, heart, and testis and with earliest detectable message in 7-day-old embryos. In situ hybridization showed prominent ocular expression during mouse embryonic development. Optn colocalizes with vesicular structures near the nucleus and is expressed in anterior segment, retina, and optic nerve blood vessels. Gene and protein ocular profiling of Optn is a prerequisite for developing a mouse model for glaucoma.

Amino Acid Sequence↗

PubMed2005

Analysis of rare variants and common haplotypes in the optineurin gene in Swedish glaucoma cases.

OBJECTIVE: Glaucoma, a leading cause of blindness in the world, is characterized by neuropathy of the retinal ganglion cells and the optic nerve. Recently, sequence alterations in the optineurin gene were shown to be associated with the disease in families with primarily normal tension glaucoma. METHODS: In the present study, 200 patients with primary open-angle glaucoma, 200 patients with exfoliative glaucoma, and 200 matched controls were tested for alterations in the coding sequences using denaturing high-performance liquid chromatography and sequencing. In addition, single nucleotide polymorphisms distributed throughout the gene were typed and haplotypes were constructed. RESULTS: No disease-causing alterations were found in either of the patient cohorts. The risk-associated allele M98K was found in equal amounts in both patients and controls. Analysis of haplotype frequencies and distribution revealed high haplotype diversity but no differences between patients and controls. CONCLUSION: These experiments show no association between optineurin and our Swedish cohorts of high-pressure glaucoma cases, either in coding sequence or in haplotype frequency and distribution.

Adult↗

PubMed2005

Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene.

PURPOSE: To investigate the clinical features of subjects with glaucoma with the E50K mutation in the optineurin (OPTN) gene and to compare the onset, severity, and clinical course of these patients with a control group of subjects with glaucoma without this mutation. METHODS: The phenotype of well-characterized subjects from Moorfields Eye Hospital, London, who had been identified as carrying the OPTN E50K mutation was examined. A wide range of structural, psychophysical, and demographic factors were then compared with those in a control group of subjects with glaucoma without this mutation. RESULTS: Eleven subjects with glaucoma with the E50K mutation (nine in two families and two sporadic cases) were studied. All 11 subjects had normal tension glaucoma (NTG), with presenting and highest IOP of 15.3 +/- 3.0 and 16.5 +/- 2.5 mm Hg (+/-SD) on diurnal testing. Compared with 87 NTG control subjects who did not have this mutation, subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area (+/-SD; 0.5 +/- 0.28 mm2, P = 0.001) at diagnosis. The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields. In addition, seven E50K mutation-carrying individuals in two families (age range, 23-58 years) presented with normal optic discs and visual fields and, as yet, no signs of glaucoma. CONCLUSIONS: In this study, subjects with glaucoma who had the OPTN E50K mutation were found to have NTG that appeared to be more severe than that in a control group of subjects with NTG without this mutation. The findings emphasize the importance of early detection and treatment of glaucoma in such individuals, to minimize visual loss.

Adult↗

PubMed2005

Molecular cloning and expression profiling of optineurin in the rhesus monkey.

PURPOSE: It has been shown that mutations in the optineurin (OPTN) gene are involved in the etiology of adult-onset primary open-angle glaucoma (POAG). In view of close similarities between human and nonhuman primate ocular development and function, the rhesus monkey is considered a suitable model for human visual system research. Therefore, this study was conducted to clone the orthologue of the human OPTN gene in the rhesus monkey (Rh-OPTN) and to determine its genomic organization. A further purpose was to establish Rh-OPTN protein expression profiles and tissue distribution in the rhesus anterior segment, retina, and optic nerve. METHODS: The Rh-OPTN gene was cloned and its genomic structure determined. The mRNA expression pattern was examined by Northern blot analysis. The protein's cellular localization, ocular expression, and tissue distribution were established by immunolabeling. RESULTS: The Rh-OPTN gene has 13 exons and encodes for a 571-amino-acid protein. Both cDNA and amino acid sequences are 96% identical with the human OPTN. Northern blot analysis revealed prominent expression of two different transcripts in heart, brain, kidney, lung, spleen, skeletal muscle, and small intestine. Cellular and tissue distribution of Rh-OPTN protein were highly similar to its human and mouse homologous proteins. CONCLUSIONS: The optineurin gene and protein are evolutionary conserved between humans and the rhesus monkey. High similarity of ocular expression and tissue distribution between the two optineurin proteins suggests that this nonhuman primate is a suitable model for the pathophysiology and treatment of human glaucomatous optic neuropathy.

Amino Acid Sequence↗

PubMed2004

Expression of cytochrome P4501b1 (Cyp1b1) during early murine development.

PURPOSE: To examine the embryonic expression of cytochrome P4501b1 (Cyp1b1) gene by whole mount in situ hybridization. METHODS: FVB/NcrlBR mouse embryos staged at 9.5, 10.5, and 11.5 dpc were obtained by timed breeding experiments. Antisense and sense RNA probes labeled with digoxigenin UTP were generated by in vitro transcription of an 848 bp Cyp1b1 cDNA fragment that was subcloned into transcription vector pCRII-TOPO. The digoxigenin labeled RNA was localized using an alkaline phosphatase conjugated anti-digoxigenin Fab fragment. Colorimetric detection of the digoxigenin labeled probe was performed with substrate solution containing 4-nitro-blue tetrazolium chloride (NBT) and 5-bromo-4-chloro-3-indolyl phosphate (BCIP). RESULTS: During early stages of murine development Cyp1b1 mRNA was detected in the developing eye, hindbrain, branchial arches, forelimb bud, ligaments supporting the liver primordium and developing kidney. In the eye and forelimb bud Cyp1b1 displayed restricted expression along the axes of development. In the developing eye Cyp1b1 exhibited dorsal expression with respect to the dorso-distal/proximo-ventral axis and anterior expression with respect to the anterior-nasal/posterior-temporal axis. In the forelimb bud Cyp1b1 expression was localized posteriorly. The polarity of Cyp1b1 expression was lost at 11.5 dpc, at which time expression was additionally seen in ventral (eye) and anterior (forelimb bud) areas. CONCLUSIONS: The spatio-temporal expression patterns observed in this study suggest that during early stages of murine development, Cyp1b1 participates in establishment and/or maintenance of polarity along the axes of embryonic development. Expression of Cyp1b1 in the dorso-distal end of the optic cup, from which the ciliary body and iris are derived, correlates with the expression patterns seen in adult tissues and the abnormal development of these structures as part of the glaucoma phenotypes resulting from Cyp1b1 mutations.

Animals↗

PubMed2003

Optineurin in primary open angle glaucoma.

The authors' initial estimate indicated that mutations in Optineurin are responsible for a significant proportion of LPG/POAG families. Currently, there are up to 1.2 million persons with LPG and up to 2.47 million persons with POAG in the United States alone. Perhaps twice as many individuals are already affected with this condition without any identifiable clinical signs or symptoms. Investigators are eagerly awaiting confirmation of OPTN mutations in other glaucoma populations. Although additional mutations have already been identified in the sporadic cases of LPG, the significance of this gene in high-pressure POAG requires more intensive investigation. Limited data on partial screening of this gene indicate that OPTN mutations are responsible for a limited number of cases of high-pressure POAG. If the reported mutation rates of OPTN in the LPG group can be confirmed in other LPG or POAG patients, then this gene would be useful in diagnosing presymptomatic persons many decades before they develop this silent and blinding eye condition. Early identification of such at-risk patients would provide an opportunity for immediate targeted medical treatments and specific glaucoma therapy that might significantly delay or completely stop the gradual progression of this condition. Therefore, identification of glaucoma-causing genes such as Myocilin, Optineurin, and others could provide molecular diagnostic tools for this category of optic neuropathy. Although patients with advanced glaucoma will not directly benefit from the use of such molecular diagnostic tools, their immediate family members could certainly benefit from the identification of the cause of the glaucoma decades before the first manifestation of the disease. In summary, a series of mutations in the Optineurin gene have been shown to be the principal cause of adult-onset LPG/POAG phenotype in certain pedigrees. The exact mechanisms through which these mutations lead to the development of glaucoma require additional functional study. The existing evidence suggests that direct interaction of Optineurin with E3-14.7K protein probably utilizes TNF-alpha or Fas-ligand pathways to mediate apoptosis, inflammation, or vasoconstriction. Optineurin also functions through its interactions with other proteins in cellular morphogenesis and membrane trafficking (RAB8), vesicle trafficking (Huntingtin), transcription activation (TFIIIA), and assembly or activity of two unknown kinases. Identification of Optineurin as an adult-onset glaucoma gene and its known interaction with a group of proteins provides the first opportunity to study biochemical pathways that are thought to be involved in causation of this group of eye disorders. Furthermore, identification of this gene as a contributing factor to the development of glaucoma gives a useful tool for screening of this disorder in the elderly population and other high-risk individuals. The exact impact of OPTN in the development of all glaucoma phenotypes requires future study.

Cell Cycle Proteins↗

PubMed2002

Adult-onset primary open-angle glaucoma caused by mutations in optineurin.

Primary open-angle glaucoma (POAG) affects 33 million individuals worldwide and is a leading cause of blindness. In a study of 54 families with autosomal dominantly inherited adult-onset POAG, we identified the causative gene on chromosome 10p14 and designated it OPTN (for "optineurin"). Sequence alterations in OPTN were found in 16.7% of families with hereditary POAG, including individuals with normal intraocular pressure. The OPTN gene codes for a conserved 66-kilodalton protein of unknown function that has been implicated in the tumor necrosis factor-alpha signaling pathway and that interacts with diverse proteins including Huntingtin, Ras-associated protein RAB8, and transcription factor IIIA. Optineurin is expressed in trabecular meshwork, nonpigmented ciliary epithelium, retina, and brain, and we speculate that it plays a neuroprotective role.

Adult↗