A Single Amino Acid Substitution (Cys249Trp) in Crb1 Causes Retinal Degeneration and Deregulates Expression of Pituitary Tumor Transforming Gene Pttg1
| Autor: | Inge Versteeg, Willem Kamphuis, Chris J. McCabe, Wendy M. Aartsen, Felix Tonagel, Jan Wijnholds, Serge A. van de Pavert, Anna Malysheva, Jan Meuleman, Mathias W. Seeliger |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Retinal degeneration
Molecular Sequence Data Nerve Tissue Proteins Biology Mice Retinitis pigmentosa medicine Animals Humans Amino Acid Sequence Cysteine Pigmented paravenous retinochoroidal atrophy Eye Proteins Regulation of gene expression Genetics Mice Knockout Retina CRB1 General Neuroscience Retinal Degeneration Tryptophan Membrane Proteins Articles medicine.disease Molecular biology Neoplasm Proteins Protein Structure Tertiary Securin medicine.anatomical_structure Amino Acid Substitution Gene Expression Regulation sense organs Muller glia Retinal Dystrophies Retinitis Pigmentosa |
| Popis: | Different mutations in the human Crumbs homolog-1 (CRB1) gene cause a variety of retinal dystrophies, such as Leber congenital amaurosis, early onset retinitis pigmentosa (e.g., RP12), RP with Coats-like exudative vasculopathy, and pigmented paravenous retinochoroidal atrophy. Loss of Crb1 leads to displaced photoreceptors and focal degeneration of all neural layers attributable to loss of adhesion between photoreceptors and Müller glia cells. To gain insight into genotype–phenotype relationship, we generatedCrb1C249Wmice that harbor an amino acid substitution (Cys249Trp) in the extracellular sixth calcium-binding epidermal growth factor domain of Crb1. Our analysis showed that Crb1C249Was wild-type protein trafficked to the subapical region adjacent to adherens junctions at the outer limiting membrane (OLM). Hence, these data suggest correct trafficking of the corresponding mutant CRB1 in RP12 patients.Crb1C249Wmice showed loss of photoreceptors in the retina, relatively late compared with mice lacking Crb1. Scanning laser ophthalmoscopy revealed autofluorescent dots that presumably represent layer abnormalities after OLM disturbance. Gene expression analyses revealed lower levels of pituitary tumor transforming gene 1 (Pttg1) transcripts inCrb1C249W/−knock-in andCrb1−/−knock-out compared with control retinas. Exposure to white light decreased levels ofPttg1inCrb1mutant retinas. We hypothesize deregulation ofPttg1expression attributable to a C249W substitution in the extracellular domain of Crb1. |
| Databáze: | OpenAIRE |
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