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Human Molecular Genetics Advance Access originally published online on July 15, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 17 2179-2189
DOI: 10.1093/hmg/ddg232
© 2003 Oxford University Press

CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina

Adrienne K. Mehalow1,{ddagger}, Shuhei Kameya1,{ddagger},{dagger}, Richard S. Smith1,{ddagger}, Norman L. Hawes1,{ddagger}, James M. Denegre1, James A. Young1, Lesley Bechtold1, Neena B. Haider1, Ulrich Tepass2, John R. Heckenlively3, Bo Chang1, Jürgen K. Naggert1 and Patsy M. Nishina1,*

1The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA, 2Department of Zoology, University of Toronto, Toronto, Ontario, Canada M5S 3G5 and 3Jules Stein Eye Institute, Harbor-UCLA Medical Center, Torrance, CA 90095, USA

Received May 2, 2003; Revised June 27, 2003; Accepted July 5, 2003

Mutations within the CRB1 gene have been shown to cause human retinal diseases including retinitis pigmentosa and Leber congenital amaurosis. We have recently identified a mouse model, retinal degeneration 8 (rd8) with a single base deletion in the Crb1 gene. This mutation is predicted to cause a frame shift and premature stop codon which truncates the transmembrane and cytoplasmic domain of CRB1. Like in Drosophila crumbs (crb) mutants, staining for adherens junction proteins known to localize to the external limiting membrane, the equivalent of the zonula adherens in the mammalian retina, is discontinuous and fragmented. Shortened photoreceptor inner and outer segments are observed as early as 2 weeks after birth, suggesting a developmental defect in these structures rather than a degenerative process. Photoreceptor degeneration is observed only within regions of retinal spotting, which is seen predominantly in the inferior nasal quadrant of the eye, and is caused by retinal folds and pseudorosettes. Photoreceptor dysplasia and degeneration in Crb1 mutants strongly vary with genetic background, suggesting that the variability in phenotypes of human patients that carry mutations in CRB1 may be due to interactions with background modifiers in addition to allelic variations. The Crb1rd8 mouse model will facilitate the analysis of Crb1 function in the neural retina and the identification of interacting factors as candidate retinal disease genes.

* To whom correspondence should be addressed. Tel: +1 2072886383; Fax: +1 2072886077; Email: pmn{at}aretha.jax.org

{dagger} Present address: Department of Ophthalmology, Akita University School of Medicine, Akita 010-8543, Japan.

{ddagger} The authors wish it to be known that, in their opinion, the first four authors should be regarded as joint First Authors.


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