QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, January 17, 2007, 27(3):564-573; doi:10.1523/JNEUROSCI.3496-06.2007

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by van de Pavert, S. A. Articles by Wijnholds, J. Search for Related Content PubMed PubMed Citation Articles by van de Pavert, S. A. Articles by Wijnholds, J.

 Previous Article  |  Next Article 

Neurobiology of Disease
A Single Amino Acid Substitution (Cys249Trp) in Crb1 Causes Retinal Degeneration and Deregulates Expression of Pituitary Tumor Transforming Gene Pttg1

Serge A. van de Pavert,¹ Jan Meuleman,¹ Anna Malysheva,¹ Wendy M. Aartsen,¹ Inge Versteeg,¹ Felix Tonagel,⁴ Willem Kamphuis,² Chris J. McCabe,³ Mathias W. Seeliger,⁴ and Jan Wijnholds¹

Departments of ¹Neuromedical Genetics and ²Molecular Ophthalmogenetics, The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands, ³Division of Medical Sciences, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TH, United Kingdom, and ⁴Retinal Electrodiagnostics Research Group, Department of Ophthalmology II, University of Tübingen, D-72076 Tübingen, Germany

Correspondence should be addressed to Dr. J. Wijnholds, The Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands. Email: j.wijnholds{at}nin.knaw.nl

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 generated Crb1^C249W mice that harbor an amino acid substitution (Cys249Trp) in the extracellular sixth calcium-binding epidermal growth factor domain of Crb1. Our analysis showed that Crb1^C249W as 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. Crb1^C249W mice 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 in Crb1^C249W/– knock-in and Crb1^–/– knock-out compared with control retinas. Exposure to white light decreased levels of Pttg1 in Crb1 mutant retinas. We hypothesize deregulation of Pttg1 expression attributable to a C249W substitution in the extracellular domain of Crb1.

Key words: adhesion; blindness; retinal degeneration; knock-out mice; mutant; retina; photoreceptors; retinitis pigmentosa (RP); Leber congenital amaurosis (LCA); Müller glia cells

---

Received Aug. 11, 2006; revised Nov. 16, 2006; accepted Nov. 19, 2006.

Correspondence should be addressed to Dr. J. Wijnholds, The Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands. Email: j.wijnholds{at}nin.knaw.nl

This article has been cited by other articles:

				J. A. Davis, P. A. Handford, and C. Redfield The N1317H Substitution Associated with Leber Congenital Amaurosis Results in Impaired Interdomain Packing in Human CRB1 Epidermal Growth Factor-like (EGF) Domains J. Biol. Chem., September 28, 2007; 282(39): 28807 - 28814. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help