Generation and Characterization of a Murine Model of Bietti Crystalline Dystrophy

Lockhart, Catherine M; Nakano, Mariko; Rettie, Allan E.; Kelly, Edward J.

doi:10.1167/iovs.13-13717

Cited by 36 publications

(51 citation statements)

References 52 publications

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“…This relative dissociation between the abnormalities at the photoreceptor outer segment-RPE layer in the setting of a preserved ONL lends supports to the hypothesis that these are the structures primarily affected by the molecular defect. 12, 21 Abnormalities of the apical RPE with loss of melanin may also explain the widespread abnormalities observed on NIR-FAF, which were less extensive on SW-FAF. 12 Choroidal thickness was normal in regions of obvious outer segment-RPE change suggesting a sequence where choroidal changes follow RPE and photoreceptor abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…A recently developed animal model of the disease, the Cyp4v3 −/− mouse, recapitulates the human phenotype and represents a landmark step forward in the study of the disease. 12 We hereby present a molecularly confirmed (compound heterozygote for two known mutations in CYP4V2 ) patient with BCD complicated by CNV at a relatively early stage of the disease, which permitted a glimpse into the early functional and structural changes, particularly in the setting of this neovascular complication. We used en face and cross-sectional retinal imaging in combination with co-localized psychophysical measures of retinal function, which we hope contribute to the current mechanistic hypotheses of this rare condition.…”

Section: Introductionmentioning

confidence: 96%

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Detailed functional and structural phenotype of Bietti crystalline dystrophy associated with mutations in CYP4V2 complicated by choroidal neovascularization

Fuerst

Serrano

Han

et al. 2016

Ophthalmic Genetics

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Purpose To describe in detail the phenotype of a patient with Bietti crystalline dystrophy (BCD) complicated by choroidal neovascularization (CNV) and the response to intravitreal Bevacizumab (Avastin ®; Genentech/Roche). Methods A 34-year-old woman with BCD and mutations in CYP4V2 (c.802-8_806del13/p.H331P:c992A>C) underwent a complete ophthalmic examination, full-field flash electroretinography (ERG), kinetic and two-color dark-adapted perimetry, and dark-adaptometry. Imaging was performed with spectral domain optical coherence tomography (SD-OCT), near infrared (NIR) and short wavelength (SW) fundus autofluorescence (FAF), and fluorescein angiography (FA). Results Best-corrected visual acuity (BCVA) was 20/20 and 20/60 for the right and left eye, respectively. There were corneal paralimbal crystal-like deposits. Kinetic fields were normal in peripheral extent. Retinal crystals were most obvious on NIR-reflectance and corresponded with hyperreflectivities within the RPE on SD-OCT. There was parafoveal/perifoveal hypofluorescence on SW-FAF and NIR-FAF. Rod > cone sensitivity loss surrounded fixation and extended to ~10° of eccentricity corresponding to regions of photoreceptor outer segment-retinal pigmented epithelium (RPE) interdigitation abnormalities. The outer nuclear layer was normal in thickness. Recovery of sensitivity following a ~76% rhodopsin bleach was normal. ERGs were normal. A subretinal hemorrhage in the left eye co-localized with elevation of the RPE on SD-OCT and leakage on FA, suggestive of CNV. Three monthly intravitreal injections of Bevacizumab led to restoration of BCVA to baseline (20/25). Conclusion Crystals in BCD were predominantly located within the RPE. Photoreceptor outer segment and apical RPE abnormalities underlie the relatively extensive retinal dysfunction observed in relatively early-stage BCD. Intravitreal Bevacizumab was effective in treating CNV in this setting.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Detailed functional and structural phenotype of Bietti crystalline dystrophy associated with mutations in CYP4V2 complicated by choroidal neovascularization

Fuerst

Serrano

Han

et al. 2016

Ophthalmic Genetics

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“…54 Recently, a Cyp4v3 (the murine ortholog to human CYP4V2) knockout mouse was created. 56 The Cyp4v3 −/− mouse recapitulates the characteristic features of corneoretinal crystal accumulation and systemic dyslipidemia observed in BCD patients. 57 Furthermore, some PUFA-derived metabolites, such as resolvin and protectin, possess anti-inflammatory and immunoregulatory signaling properties and may be disrupted in BCD patients.…”

Section: Role Of Cyp4v2 In Fatty Acid Metabolismmentioning

confidence: 95%

Genetics of Bietti Crystalline Dystrophy

Ng¹,

Lai²,

Ng³

et al. 2016

Asia-Pacific Journal of Ophthalmology

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Bietti crystalline dystrophy (BCD) is an inherited retinal degenerative disease characterized by crystalline deposits in the retina, followed by progressive atrophy of the retinal pigment epithelium (RPE), choriocapillaris, and photoreceptors. CYP4V2 has been identified as the causative gene for BCD. The CYP4V2 gene belongs to the cytochrome P450 superfamily and encodes for fatty acid ω-hydroxylase of both saturated and unsaturated fatty acids. The CYP4V2 protein is localized most abundantly within the endoplasmic reticulum in the RPE and is postulated to play a role in the physiological lipid recycling system between the RPE and photoreceptors to maintain visual function. Electroretinographic assessments have revealed progressive dysfunction of rod and cone photoreceptors in patients with BCD. Several genotypes have been associated with more severe phenotypes based on clinical and electrophysiological findings. With the advent of multimodal imaging with spectral domain optical coherence tomography, fundus autofluorescence, and adaptive optics scanning laser ophthalmoscopy, more precise delineation of BCD severity and progression is now possible, allowing for the potential future development of targets for gene therapy.

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“…P450s 4B1, 4V2, and 4X1 have orthologues in other vertebrate species, whereas the P450 4A and 4F subfamilies exhibit paralogues with differences in the number of genes for these two subfamilies in other species (1,2). Although these enzymes often exhibit overlapping substrate specificities, genetic association studies link the -hydroxylase CYP4V2 to the Bietti's crystalline dystrophy, which is characterized by ocular lipid deposits (7,8), suggesting a key role for CYP4V2 in the removal of excess lipids in ocular tissues. Furthermore, CYP4F22 genetic variants are associated with lamellar ichthyosis, which reflects deficiencies in the water permeability barrier of skin (9).…”

mentioning

confidence: 99%

The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monooxygenase Complexed with Octane Discloses Several Structural Adaptations for ω-Hydroxylation

Hsu

Baer

Rettie

et al. 2017

Journal of Biological Chemistry

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Edited by Ruma BanerjeeP450 family 4 fatty acid -hydroxylases preferentially oxygenate primary C-H bonds over adjacent, energetically favored secondary C-H bonds, but the mechanism explaining this intriguing preference is unclear. To this end, the structure of rabbit P450 4B1 complexed with its substrate octane was determined by X-ray crystallography to define features of the active site that contribute to a preference for -hydroxylation. The structure indicated that octane is bound in a narrow active-site cavity that limits access of the secondary C-H bond to the reactive intermediate. A highly conserved sequence motif on helix I contributes to positioning the terminal carbon of octane for -hydroxylation. Glu-310 of this motif auto-catalytically forms an ester bond with the heme 5-methyl, and the immobilized Glu-310 contributes to substrate positioning. The preference for -hydroxylation was decreased in an E310A mutant having a shorter side chain, but the overall rates of metabolism were retained. E310D and E310Q substitutions having longer side chains exhibit lower overall rates, likely due to higher conformational entropy for these residues, but they retained high preferences for octane -hydroxylation. Sequence comparisons indicated that active-site residues constraining octane for -hydroxylation are conserved in family 4 P450s. Moreover, the heme 7-propionate is positioned in the active site and provides additional restraints on substrate binding. In conclusion, P450 4B1 exhibits structural adaptations for -hydroxylation that include changes in the conformation of the heme and changes in a highly conserved helix I motif that is associated with selective oxygenation of unactivated primary C-H bonds.Cytochrome P450 family 4 fatty acid -hydroxylases are heme-containing monooxygenases that provide pathways for the reduction of potentially toxic non-esterified fatty acids and for the elimination of excess nutritive and non-nutritive lipids by catalyzing the addition of oxygen to a C-H bond of the terminal -carbon of fatty acids (1, 2). The resulting -alcohols are generally oxidized further to produce dicarboxylic acids, but they also may be transformed to glucuronides or esterified to glycerolipids. Urinary dicarboxylic fatty acids are elevated in humans by fasting or in uncontrolled diabetes, which are conditions where adipocyte lipolysis increases the availability of non-esterified fatty acids to fuel metabolism (3). It is estimated that roughly 15% of fatty acids undergo -hydroxylation during peak periods of fatty acid catabolism (4), whereas this fraction is much smaller under conditions where concentrations of nonesterified fatty acids are low (5). Collectively, these enzymes provide pathways for the metabolic clearance of branched chain fatty acids, eicosanoids, and xenobiotic substrates such as dietary phytanic acid, drugs, toxins, and vitamins E and K (1, 2, 6).Similar to other P450 2 gene families encoding multipurpose enzymes for the elimination of xenobiotic compounds, family 4 exhibits genetic diversi...

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Generation and Characterization of a Murine Model of Bietti Crystalline Dystrophy

Abstract: Cyp4v3(-/-) mice represent a promising preclinical model that may be used to better understand the disease etiology and to evaluate pharmacotherapies for this devastating condition.

Cited by 36 publications

References 52 publications

Detailed functional and structural phenotype of Bietti crystalline dystrophy associated with mutations in CYP4V2 complicated by choroidal neovascularization

Detailed functional and structural phenotype of Bietti crystalline dystrophy associated with mutations in CYP4V2 complicated by choroidal neovascularization

Genetics of Bietti Crystalline Dystrophy

The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monooxygenase Complexed with Octane Discloses Several Structural Adaptations for ω-Hydroxylation

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