HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplementary Tables Submit a response 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 (6) Citing Articles via Google Scholar Google Scholar Articles by Guziewicz, K. E. Articles by Aguirre, G. D. Search for Related Content PubMed PubMed Citation Articles by Guziewicz, K. E. Articles by Aguirre, G. D.

Bestrophin Gene Mutations Cause Canine Multifocal Retinopathy: A Novel Animal Model for Best Disease

¹From the Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; ²Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa; ³Department of Small Animal Clinical Sciences, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; ⁴Howard Hughes Medical Institute, Iowa City, Iowa; and ⁵J.A. Baker Institute for Animal Health, Cornell University, Ithaca, New York.

PURPOSE. Canine multifocal retinopathy (cmr) is an autosomal recessive disorder of multiple dog breeds. The disease shares a number of clinical and pathologic similarities with Best macular dystrophy (BMD), and cmr is proposed as a new large animal model for Best disease.

METHODS. cmr was characterized by ophthalmoscopy and histopathology and compared with BMD-affected patients. BEST1 (alias VMD2), the bestrophin gene causally associated with BMD, was evaluated in the dog. Canine ortholog cDNA sequence was cloned and verified using RPE/choroid 5'- and 3'-RACE. Expression of the canine gene transcripts and protein was analyzed by Northern and Western blotting and immunocytochemistry. All exons and the flanking splice junctions were screened by direct sequencing.

RESULTS. The clinical phenotype and pathology of cmr closely resemble lesions of BMD. Canine VMD2 spans 13.7 kb of genomic DNA on CFA18 and shows a high level of conservation among eukaryotes. The transcript is predominantly expressed in RPE/choroid and encodes bestrophin, a 580-amino acid protein of 66 kDa. Immunocytochemistry of normal canine retina demonstrated specific localization of protein to the RPE basolateral plasma membranes. Two disease-specific sequence alterations were identified in the canine VMD2 gene: a C₇₃T stop mutation in cmr1 and a G₄₈₂A missense mutation in cmr2.

CONCLUSIONS. The authors propose these two spontaneous mutations in the canine VMD2 gene, which cause cmr, as the first naturally occurring animal model of BMD. Further development of the cmr models will permit elucidation of the complex molecular mechanism of these retinopathies and the development of potential therapies.

This article has been cited by other articles:

				K. Yu, Q. Xiao, G. Cui, A. Lee, and H. C. Hartzell The Best Disease-Linked Cl- Channel hBest1 Regulates CaV1 (L-type) Ca2+ Channels via src-Homology-Binding Domains J. Neurosci., May 28, 2008; 28(22): 5660 - 5670. [Abstract] [Full Text] [PDF]

				H. C. Hartzell, Z. Qu, K. Yu, Q. Xiao, and L.-T. Chien Molecular Physiology of Bestrophins: Multifunctional Membrane Proteins Linked to Best Disease and Other Retinopathies Physiol Rev, April 1, 2008; 88(2): 639 - 672. [Abstract] [Full Text] [PDF]

				R. F. Mullins, M. H. Kuehn, E. A. Faidley, N. A. Syed, and E. M. Stone Differential Macular and Peripheral Expression of Bestrophin in Human Eyes and Its Implication for Best Disease Invest. Ophthalmol. Vis. Sci., July 1, 2007; 48(7): 3372 - 3380. [Abstract] [Full Text] [PDF]