- R180T variant of δ-ornithine aminotransferase associated with gyrate atrophy: biochemical, computational, X-ray and NMR studies provide insight into its catalytic features. [Journal Article]
- FJFEBS J 2019 Apr 08
- Among the over 50 gyrate atrophy-causing mutations of ornithine δ-aminotransferase (OAT), the R180T involves an active site residue located at the dimer interface, which in the crystal structure of O…
Among the over 50 gyrate atrophy-causing mutations of ornithine δ-aminotransferase (OAT), the R180T involves an active site residue located at the dimer interface, which in the crystal structure of OAT complexed with 5-fluoromethylornithine engages a salt bridge with the α-carboxylate of the substrate analogue. Starting from the previous finding that no transaminase activity was detected in CHO-K1 cells expressing the R180T variant, here we try to shed light at the protein level on the structural and/or functional defects of the R180T variant. To this aim, the variant has been cloned, expressed, purified and characterized by a combination of biochemical and structural studies. Although the R180T variant shares a similar overall conformation with the wild-type, its crystal structure solved at 1.8 Ǻ reveals slight structural alterations at the active site and at the dimeric interface. These changes are consistent with the spectroscopic and kinetic results, indicating that the variant, as compared with the wild-type OAT, shows (a) an increased Km value for l-ornithine (l-Orn), (b) an altered pyridoxal 5'-phosphate binding mode and affinity and (c) an increased thermostability. In addition, the R180T mutant exhibits a remarkable loss of catalytic activity and is endowed with the ability to catalyse not only the δ-transamination but also, albeit to a lesser extent, the α-transamination of l-Orn. Overall, these data indicate that the slight structural changes caused by the R180T mutation, preventing a proper collocation of l-Orn at the active site of OAT, are responsible for the notable reduction of the catalytic efficiency. ENZYMES: Ornithine aminotransferase EC 220.127.116.11. DATABASES: 6HX7.pdb.
- Letter to the editor regarding: "cystoid macular edema secondary to gyrate atrophy in a child treated with sub-tenon injection of triamcinolone acetonide". [Journal Article]
- RJRom J Ophthalmol 2018 Oct-Dec; 62(4):317-318
- Complete primary pachydermoperiostosis: A case report from Jordan and review of literature. [Case Reports]
- CCClin Case Rep 2019; 7(2):346-352
- Complete Primary Pachydermoperiostosis is a rare syndrome that presents with skin and skeletal manifestations. Though diagnosis can be made on the basis of the classic clinical and radiological featu…
Complete Primary Pachydermoperiostosis is a rare syndrome that presents with skin and skeletal manifestations. Though diagnosis can be made on the basis of the classic clinical and radiological features, it is often missed due to variable presentations. Therefore, it is important to know about this syndrome to reach correct diagnosis.
- Inborn Errors of Metabolism: Gyrate Atrophy. [Journal Article]
- AEAdv Exp Med Biol 2018; 1085:183-185
- Gyrate atrophy is an autosomal recessive dystrophy in which night blindness starts early in the first decade of life. In the early stages, large areas of retinal pigment epithelium (RPE) and chorioca…
Gyrate atrophy is an autosomal recessive dystrophy in which night blindness starts early in the first decade of life. In the early stages, large areas of retinal pigment epithelium (RPE) and choriocapillaris (CC) atrophy in the far periphery (lobular shape, Fig. 37.1). (In choroideremia, atrophy appears in the mid periphery.) Later, these areas coalesce to form a characteristic scalloped border at the junction of healthy and diseased RPE. Myopia and subcapsular cataract are common by the end of second or third decade. Unlike in choroideremia (which is X-linked), patients with gyrate atrophy show areas of hyperpigmentation of the remaining RPE (Fig. 37.2). Patients with gyrate atrophy do not show the choroidal atrophy (as seen in choroideremia) until the late stages. Treatment includes a low-protein, arginine-restricted diet for all patients. In some cases, vitamin B6 (pyridoxine) may help in lowering plasma ornithine levels.
- Dexamethasone implant for the treatment of gyrate atrophy associated macular edema. [Letter]
- JFJ Fr Ophtalmol 2019; 42(1):e1-e4
- Cystoid macular edema secondary to gyrate atrophy in a child treated with sub-tenon injection of triamcinolone acetonide. [Case Reports]
- RJRom J Ophthalmol 2018 Jul-Sep; 62(3):246-249
- Purpose: Gyrate atrophy (GA) of the fundus is a rare, progressive metabolic disease secondary to the deficiency of the pyridoxal phosphate-dependent enzyme, ornithine aminotransferase. GA may lead t…
Purpose: Gyrate atrophy (GA) of the fundus is a rare, progressive metabolic disease secondary to the deficiency of the pyridoxal phosphate-dependent enzyme, ornithine aminotransferase. GA may lead to cystoid macular edema (CME) resulting from chronic inflammation. We aimed to report a child case with CME secondary to gyrate atrophy. Methods: Herein we presented a GA case treated with posterior sub-Tenon triamcinolone acetonide injection. Results: Optical coherence tomography examination revealed the disappearance of the macular edema that is a vision-threatening complication in GA. Conclusion: The present case showed that the posterior sub-Tenon injection of long acting steroids might be a promising treatment in CME secondary to GA.
- Metabolic follow-up of a Croatian patient with gyrate atrophy and a new mutation in the OAT gene: a case report. [Case Reports]
- BMBiochem Med (Zagreb) 2018 Oct 15; 28(3):030801
- Gyrate atrophy (GA) of the choroid and retina is a rare autosomal recessive disorder that occurs due to deficiency of the mitochondrial enzyme ornithine aminotransferase (OAT). Hyperornithinemia caus…
Gyrate atrophy (GA) of the choroid and retina is a rare autosomal recessive disorder that occurs due to deficiency of the mitochondrial enzyme ornithine aminotransferase (OAT). Hyperornithinemia causes degeneration of the retina with symptoms like myopia, reduced night vision and progressive vision loss. Our patient is a 10-year-old girl with impaired vision and strabismus. As part of the metabolic work-up, plasma amino acid analysis revealed significantly increased concentration of ornithine (1039 μmol/L; reference interval 20 - 155 μmol/L). Molecular genetic analysis revealed homozygous mutation in exon 7 of the OAT gene that has not been reported previously (c.868_870delCTT p.(Leu290del)). This in frame deletion was predicted to be deleterious by in silico software analysis. Our patient was treated with pyridoxine (vitamin B6 in a dose of 2 x 100 mg/day), low-protein diet (0.6 g/kg/day) and L-lysine supplementation which resulted in a significant reduction in plasma ornithine concentrations to 53% of the initial concentration and the ophthalmologic findings showed significant improvement. We conclude that low protein diet and lysine supplementation can lead to long-term reduction in plasma ornithine concentrations and, if started at an early age, notably slow the progression of retinal function loss in patients with GA. The effect of therapy can be reliably monitored by periodical measurement of plasma ornithine concentration. To our knowledge, this is the first report of OAT deficiency in Croatia.
- Diagnostic value of a combination of next-generation sequencing, chorioretinal imaging and metabolic analysis: lessons from a consanguineous Chinese family with gyrate atrophy of the choroid and retina stemming from a novel OAT variant. [Journal Article]
- BJBr J Ophthalmol 2019; 103(3):428-435
- CONCLUSIONS: Recruitment of a third-degree first cousin consanguineous marriage family with GACR allowed us to identify a novel pathogenic OAT variant in the Chinese population, broadening the mutation spectrum. Our findings reported the diagnostic value of a combination of NGS, retinal imaging and metabolic analysis of consanguineous marriage pedigrees in low-income/middle-income and low-incidence countries, including China, and may help to guide accurate diagnosis and treatment of this disease.
- Bevacizumab for the treatment of intraretinal cystic spaces in a patient with gyrate atrophy of the choroid and retina. [Case Reports]
- OGOphthalmic Genet 2018; 39(6):759-762
- CONCLUSIONS: Repeated intravitreal bevacizumab injections can result in anatomical and functional improvement of intraretinal cystic spaces in patients with gyrate atrophy of the choroid and retina.
New Search Next
- Shape and fluctuations of positively curved ribbons. [Journal Article]
- PRPhys Rev E 2018; 98(2-1):022502
- We study the shape and shape fluctuations of incompatible, positively curved ribbons, with a flat reference metric and a spherelike reference curvature. Such incompatible geometry is likely to occur …
We study the shape and shape fluctuations of incompatible, positively curved ribbons, with a flat reference metric and a spherelike reference curvature. Such incompatible geometry is likely to occur in many self-assembled materials and other experimental systems. Ribbons of this geometry exhibit a sharp transition between a rigid ring and an anomalously soft spring as a function of their width. As a result, the temperature dependence of these ribbons' shape is unique, exhibiting a nonmonotonic dependence of the persistence and Kuhn lengths on the temperature and width. We map the possible configuration phase space and show the existence of three phases: At high temperatures it is the ideal chain phase, where the ribbon is well described by classical models (e.g., wormlike chain model). The second phase, for cold and narrow ribbons, is the plane ergodic phase; a ribbon in this phase might be thought of as made out of segments that gyrate within an oblate spheroid with extreme aspect ratio. The third phase, for cold, wide ribbons, is a direct result of the residual stress caused by the incompatibility, called the random structured phase. A ribbon in this phase behaves on large scales as an ideal chain. However, the segments of this chain are not straight; rather they may have different shapes, mainly helices (both left and right handed) of various pitches.