8 results on '"Messchaert M"'
Search Results
2. Development and validation of an early warning score to identify COVID-19 in the emergency department based on routine laboratory tests: a multicentre case-control study.
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Boer AK, Deneer R, Maas M, Ammerlaan HSM, van Balkom RHH, Thijssen WAHM, Bennenbroek S, Leers M, Martens RJH, Buijs MM, Kerremans JJ, Messchaert M, van Suijlen JJ, van Riel NAW, and Scharnhorst V
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- Case-Control Studies, Emergency Service, Hospital, Humans, SARS-CoV-2, Tertiary Care Centers, COVID-19 diagnosis, COVID-19 epidemiology, Early Warning Score
- Abstract
Objectives: Identifying patients with a possible SARS-CoV-2 infection in the emergency department (ED) is challenging. Symptoms differ, incidence rates vary and test capacity may be limited. As PCR-testing all ED patients is neither feasible nor effective in most centres, a rapid, objective, low-cost early warning score to triage ED patients for a possible infection is developed., Design: Case-control study., Setting: Secondary and tertiary hospitals in the Netherlands., Participants: The study included patients presenting to the ED with venous blood sampling from July 2019 to July 2020 (n=10 417, 279 SARS-CoV-2-positive). The temporal validation cohort covered the period from July 2020 to October 2021 (n=14 080, 1093 SARS-CoV-2-positive). The external validation cohort consisted of patients presenting to the ED of three hospitals in the Netherlands (n=12 061, 652 SARS-CoV-2-positive)., Primary Outcome Measures: The primary outcome was one or more positive SARS-CoV-2 PCR test results within 1 day prior to or 1 week after ED presentation., Results: The resulting 'CoLab-score' consists of 10 routine laboratory measurements and age. The score showed good discriminative ability (AUC: 0.930, 95% CI 0.909 to 0.945). The lowest CoLab-score had high sensitivity for COVID-19 (0.984, 95% CI 0.970 to 0.991; specificity: 0.411, 95% CI 0.285 to 0.520). Conversely, the highest score had high specificity (0.978, 95% CI 0.973 to 0.983; sensitivity: 0.608, 95% CI 0.522 to 0.685). The results were confirmed in temporal and external validation., Conclusions: The CoLab-score is based on routine laboratory measurements and is available within 1 hour after presentation. Depending on the prevalence, COVID-19 may be safely ruled out in over one-third of ED presentations. Highly suspect cases can be identified regardless of presenting symptoms. The CoLab-score is continuous, in contrast to the binary outcome of lateral flow testing, and can guide PCR testing and triage ED patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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3. Extending the Spectrum of EYS-Associated Retinal Disease to Macular Dystrophy.
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Pierrache LHM, Messchaert M, Thiadens AAHJ, Haer-Wigman L, de Jong-Hesse Y, van Zelst-Stams WAG, Collin RWJ, Klaver CCW, and van den Born LI
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- Adult, Aged, Aged, 80 and over, DNA Mutational Analysis, Electroretinography, Eye Proteins metabolism, Female, Homozygote, Humans, Macular Degeneration diagnosis, Macular Degeneration metabolism, Male, Middle Aged, Pedigree, Phenotype, Retina metabolism, Retina physiopathology, Retinitis Pigmentosa diagnosis, Retinitis Pigmentosa metabolism, Tomography, Optical Coherence, Young Adult, Eye Proteins genetics, Macular Degeneration genetics, Mutation, RNA, Messenger genetics, Retina pathology, Retinitis Pigmentosa genetics, Visual Acuity
- Abstract
Purpose: To assess the phenotypic variability and natural course of inherited retinal diseases (IRDs) caused by EYS mutations., Methods: Multiethnic cohort study (N = 30) with biallelic EYS variants from a clinical IRD database (retinitis pigmentosa [RP], N = 27; cone-rod dystrophy [CRD], N = 1; and macular dystrophy, N = 2). In vitro minigene splice assay was performed to determine the effect on EYS pre-mRNA splicing of the c.1299+5_1299+8del variant in macular dystrophy patients., Results: We found 27 different EYS variants in RP patients and 7 were novel. The rate of visual field loss of the V4e isopter area was -0.84 ± 0.44 ln(deg2) per year, and the rate of visual acuity loss was 0.75 Early Treatment Diabetic Retinopathy Study letters per year. Ellipsoid zone width was correlated with area of the hyperautofluorescent ring, with rs = 0.78 and P < 0.001. Rate of decline in ellipsoid zone width was -57 ± 17 μm per year (P < 0.01) (n = 14) or -3.69% ± 0.51% from baseline per year (P < 0.001). An isolated CRD patient carried a homozygous EYS variant (c.9405T>A), previously identified in RP patients. Two siblings with macular dystrophy carried compound heterozygous EYS variants: c.1299+5_1299+8del and c.6050G>T. The former was novel and shown to result in skipping of exon 8, and the latter was a known RP variant., Conclusions: We report on EYS-associated macular dystrophy, extending the spectrum of EYS-associated IRDs. We observed heterogeneity between RP patients in age of onset and disease progression. Identical EYS variants were found in cases with RP, CRD, and macular dystrophy. Screening for EYS variants in CRD and macular dystrophy patients might increase the diagnostic yield in previously unsolved cases.
- Published
- 2019
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4. Eyes shut homolog is important for the maintenance of photoreceptor morphology and visual function in zebrafish.
- Author
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Messchaert M, Dona M, Broekman S, Peters TA, Corral-Serrano JC, Slijkerman RWN, van Wijk E, and Collin RWJ
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- Animals, CRISPR-Cas Systems, DNA Mutational Analysis, Electroretinography, Genes, Recessive, Genotype, Humans, Larva, Mutation, Protein Domains, RNA analysis, Retina physiology, Retinal Cone Photoreceptor Cells metabolism, Retinitis Pigmentosa genetics, Rhodopsin metabolism, Transducin metabolism, Zebrafish, Eye Proteins genetics, Eye Proteins physiology, Vision, Ocular, Zebrafish Proteins genetics, Zebrafish Proteins physiology
- Abstract
Mutations in eyes shut homolog (EYS), a gene predominantly expressed in the photoreceptor cells of the retina, are among the most frequent causes of autosomal recessive (ar) retinitis pigmentosa (RP), a progressive retinal disorder. Due to the absence of EYS in several rodent species and its retina-specific expression, still little is known about the exact function of EYS and the pathogenic mechanism underlying EYS-associated RP. We characterized eys in zebrafish, by RT-PCR analysis on zebrafish eye-derived RNA, which led to the identification of a 8,715 nucleotide coding sequence that is divided over 46 exons. The transcript is predicted to encode a 2,905-aa protein that contains 39 EGF-like domains and five laminin A G-like domains, which overall shows 33% identity with human EYS. To study the function of EYS, we generated a stable eysrmc101/rmc101 mutant zebrafish model using CRISPR/Cas9 technology. The introduced lesion is predicted to result in premature termination of protein synthesis and lead to loss of Eys function. Immunohistochemistry on retinal sections revealed that Eys localizes at the region of the connecting cilium and that both rhodopsin and cone transducin are mislocalized in the absence of Eys. Electroretinogram recordings showed diminished b-wave amplitudes in eysrmc101/rmc101 zebrafish (5 dpf) compared to age- and strain-matched wild-type larvae. In addition, decreased locomotor activity in response to light stimuli was observed in eys mutant larvae. Altogether, our study shows that absence of Eys leads to a disorganized retinal architecture and causes visual dysfunction in zebrafish., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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5. C2orf71a/pcare1 is important for photoreceptor outer segment morphogenesis and visual function in zebrafish.
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Corral-Serrano JC, Messchaert M, Dona M, Peters TA, Kamminga LM, van Wijk E, and Collin RWJ
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- Animals, Animals, Genetically Modified, Electroretinography, Immunohistochemistry, Mesothelin, Mice, Morphogenesis genetics, Morphogenesis physiology, Photic Stimulation, Zebrafish Proteins genetics, Zebrafish embryology, Zebrafish metabolism, Zebrafish Proteins metabolism
- Abstract
Mutations in C2orf71 are causative for autosomal recessive retinitis pigmentosa and occasionally cone-rod dystrophy. We have recently discovered that the protein encoded by this gene is important for modulation of the ciliary membrane through the recruitment of an actin assembly module, and have therefore renamed the gene to PCARE (photoreceptor cilium actin regulator). Here, we report on the identification of two copies of the c2orf71/pcare gene in zebrafish, pcare1 and pcare2. To study the role of the gene most similar to human PCARE, pcare1, we have generated a stable pcare1 mutant zebrafish model (designated pcare1
rmc100/rmc100 ) in which the coding sequence was disrupted using CRISPR/Cas9 technology. Retinas of both embryonic (5 dpf) and adult (6 mpf) pcare1rmc100/rmc100 zebrafish display a clear disorganization of photoreceptor outer segments, resembling the phenotype observed in Pcare-/- mice. Optokinetic response and visual motor response measurements indicated visual impairment in pcare1rmc100/rmc100 zebrafish larvae at 5 dpf. In addition, electroretinogram measurements showed decreased b-wave amplitudes in pcare1rmc100/rmc100 zebrafish as compared to age- and strain-matched wild-type larvae, indicating a defect in the transretinal current. Altogether, our data show that lack of pcare1 causes a retinal phenotype in zebrafish and indicate that the function of the PCARE gene is conserved across species.- Published
- 2018
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6. EYS mutation update: In silico assessment of 271 reported and 26 novel variants in patients with retinitis pigmentosa.
- Author
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Messchaert M, Haer-Wigman L, Khan MI, Cremers FPM, and Collin RWJ
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- Alleles, Genotype, Humans, Mutation, Missense genetics, Phenotype, RNA Splice Sites genetics, Eye Proteins genetics, Mutation genetics, Retinitis Pigmentosa genetics
- Abstract
Mutations in Eyes shut homolog (EYS) are one of the most common causes of autosomal recessive (ar) retinitis pigmentosa (RP), a progressive blinding disorder. The exact function of the EYS protein and the pathogenic mechanisms underlying EYS-associated RP are still poorly understood, which hampers the interpretation of the causality of many EYS variants discovered to date. We collected all reported EYS variants present in 377 arRP index cases published before June 2017, and uploaded them in the Leiden Open Variation Database (www.LOVD.nl/EYS). We also describe 36 additional index cases, carrying 26 novel variants. Of the 297 unique EYS variants identified, almost half (n = 130) are predicted to result in premature truncation of the EYS protein. Classification of all variants using the American College of Medical Genetics and Genomics guidelines revealed that the predicted pathogenicity of these variants cover the complete spectrum ranging from likely benign to pathogenic, although especially missense variants largely fall in the category of uncertain significance. Besides the identification of likely benign alleles previously reported as being probably pathogenic, our comprehensive analysis underscores the need of functional assays to assess the causality of EYS variants, in order to improve molecular diagnostics and counseling of patients with EYS-associated RP., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2018
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7. In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery.
- Author
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Garanto A, Chung DC, Duijkers L, Corral-Serrano JC, Messchaert M, Xiao R, Bennett J, Vandenberghe LH, and Collin RW
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- Animals, Antigens, Neoplasm therapeutic use, Blindness genetics, Blindness pathology, Cell Cycle Proteins, Cytoskeletal Proteins, Dependovirus genetics, Disease Models, Animal, Exons genetics, Humans, Leber Congenital Amaurosis genetics, Leber Congenital Amaurosis pathology, Mice, Mutation, Neoplasm Proteins therapeutic use, Oligonucleotides, Antisense genetics, Phenotype, RNA Splice Sites genetics, RNA Splicing genetics, Retina drug effects, Retina pathology, Antigens, Neoplasm genetics, Blindness therapy, Genetic Therapy, Leber Congenital Amaurosis therapy, Neoplasm Proteins genetics, Oligonucleotides, Antisense administration & dosage
- Abstract
Leber congenital amaurosis (LCA) is a severe disorder resulting in visual impairment usually starting in the first year of life. The most frequent genetic cause of LCA is an intronic mutation in CEP290 (c.2991 + 1655A > G) that creates a cryptic splice donor site resulting in the insertion of a pseudoexon (exon X) into CEP290 mRNA. Previously, we showed that naked antisense oligonucleotides (AONs) effectively restored normal CEP290 splicing in patient-derived lymphoblastoid cells. We here explore the therapeutic potential of naked and adeno-associated virus (AAV)-packaged AONs in vitro and in vivo In both cases, AON delivery fully restored CEP290 pre-mRNA splicing, significantly increased CEP290 protein levels and rescued a ciliary phenotype present in patient-derived fibroblast cells. Moreover, administration of naked and AAV-packaged AONs to the retina of a humanized mutant Cep290 mouse model, carrying the intronic mutation, showed a statistically significant reduction of exon X-containing Cep290 transcripts, without compromising the retinal structure. Together, our data highlight the tremendous therapeutic prospective of AONs for the treatment of not only CEP290-associated LCA but potentially many other subtypes of retinal dystrophy caused by splicing mutations., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2016
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8. Alternating Hemiplegia of Childhood mutations have a differential effect on Na(+),K(+)-ATPase activity and ouabain binding.
- Author
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Weigand KM, Messchaert M, Swarts HG, Russel FG, and Koenderink JB
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- Animals, Cell Line, Genetic Predisposition to Disease, Hemiplegia enzymology, Humans, Models, Molecular, Phenotype, Phosphorylation, Potassium metabolism, Protein Binding, Protein Structure, Secondary, Sf9 Cells, Sodium-Potassium-Exchanging ATPase chemistry, Sodium-Potassium-Exchanging ATPase genetics, Spodoptera, Hemiplegia genetics, Hemiplegia metabolism, Mutation, Ouabain metabolism, Sodium-Potassium-Exchanging ATPase metabolism
- Abstract
De novo mutations in ATP1A3, the gene encoding the α3-subunit of Na(+),K(+)-ATPase, are associated with the neurodevelopmental disorder Alternating Hemiplegia of Childhood (AHC). The aim of this study was to determine the functional consequences of six ATP1A3 mutations (S137Y, D220N, I274N, D801N, E815K, and G947R) associated with AHC. Wild type and mutant Na(+),K(+)-ATPases were expressed in Sf9 insect cells using the baculovirus expression system. Ouabain binding, ATPase activity, and phosphorylation were absent in mutants I274N, E815K and G947R. Mutants S137Y and D801N were able to bind ouabain, although these mutants lacked ATPase activity, phosphorylation, and the K(+)/ouabain antagonism indicative of modifications in the cation binding site. Mutant D220N showed similar ouabain binding, ATPase activity, and phosphorylation to wild type Na(+),K(+)-ATPase. Functional impairment of Na(+),K(+)-ATPase in mutants S137Y, I274N, D801N, E815K, and G947R might explain why patients having these mutations suffer from AHC. Moreover, mutant D801N is able to bind ouabain, whereas mutant E815K shows a complete loss of function, possibly explaining the different phenotypes for these mutations., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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